Harnessing Immunity to Treat Advanced Thyroid Cancer

Abstract

The incidence of thyroid cancer (TC) has increased over the past 30 years. Although differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thyroidectomy followed by radioiodine therapy (RAI), 5–10% of patients develop metastasis. Anaplastic thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs. Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy, and their combinations have enabled us to overcome immune suppression and activate antitumor immune cells. This review summarizes current findings regarding the immune microenvironment, immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential efficacy of immunotherapy.

Full text

Citation: Komatsuda, H.; Kono, M.;
Wakisaka, R.; Sato, R.; Inoue, T.;
Kumai, T.; Takahara, M. Harnessing
Immunity to Treat Advanced Thyroid
Cancer. Vaccines 2024,12, 45. https://
doi.org/10.3390/vaccines12010045
Academic Editor: Subbaya
Subramanian
Received: 20 November 2023
Revised: 26 December 2023
Accepted: 29 December 2023
Published: 30 December 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Review
Harnessing Immunity to Treat Advanced Thyroid Cancer
Hiroki Komatsuda 1, † , Michihisa Kono 1, 2, † , Risa Wakisaka 1, Ryosuke Sato 1, Takahiro Inoue 1,
Takumi Kumai 1, 3, * and Miki Takahara 1,3
1
Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa 078-8510,
Japan; komatsuda@asahikawa-med.ac.jp (H.K.); mkono@asahikawa-med.ac.jp (M.K.);
r-wakisaka@asahikawa-med.ac.jp (R.W.); rsato@asahikawa-med.ac.jp (R.S.); takapiro9242@gmail.com (T.I.);
miki@asahikawa-med.ac.jp (M.T.)
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
3Department of Innovative Head & Neck Cancer Research and Treatment, Asahikawa Medical University,
Asahikawa 078-8510, Japan
*Correspondence: t-kumai@asahikawa-med.ac.jp; Tel.: +81-166-68-2554; Fax: +81-166-68-2559
†These authors contributed equally to this article.
Abstract: The incidence of thyroid cancer (TC) has increased over the past 30 years. Although
differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thy-
roidectomy followed by radioiodine therapy (RAI), 5–10% of patients develop metastasis. Anaplastic
thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to
date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or
non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs.
Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot
malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-
associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and
dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and
indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances
in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy,
and their combinations have enabled us to overcome immune suppression and activate antitumor
immune cells. This review summarizes current findings regarding the immune microenvironment,
immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential
efficacy of immunotherapy.
Keywords: thyroid cancer; immunotherapy; adjuvant; targeted therapy; peptide vaccine
1. Introduction
Thyroid cancer (TC) is a major cancer worldwide, and its incidence has consistently
increased over the past 30 years partly due to the advances in diagnostic techniques [
1
].
TC predominantly affects women throughout the world. Despite its rising incidence,
mortality from TC remains relatively low [
1
]. TC is classified into four categories: papillary
thyroid cancer (PTC), follicular thyroid cancer (FTC), medullary thyroid cancer (MTC), and
anaplastic thyroid cancer (ATC). PTC and FTC are differentiated thyroid cancers (DTC) that
account for >90% of all TC [
2
]. Hemithyroidectomy and total thyroidectomy followed by
radioiodine therapy (RAI) are widely accepted standard treatments for DTC [
3
]. However,
the prognosis of ATC is poor, with a median overall survival (OS) of less than 7 months
despite multiple treatment approaches [
4
]. In recent years, tyrosine kinase inhibitors
(TKIs) have been applied to RAI-resistant or RAI-irresponsive TC and are effective in
suppressing these diseases. However, in most cases, TC eventually develops resistance to
TKI. Immunotherapy has attracted the attention of clinicians for the treatment of patients
with TKI-resistant TC. Although this treatment is promising for several cancer types,
its immunogenicity in thyroid cancer has not been fully investigated. ATC and half of
Vaccines 2024,12, 45. https://doi.org/10.3390/vaccines12010045 https://www.mdpi.com/journal/vaccines

Vaccines 2024,12, 45 2 of 17
PTC are considered immune-hot malignancies based on the NanoString platform [
5
],
suggesting that immunotherapy is a promising treatment for advanced TC. This review
explores the immunological features of advanced TC and highlights the potential efficacy
of immunotherapy.
2. Immunity in TC Micromilieu
2.1. Antitumor Immune Cells
Natural killer (NK) cells account for the innate immunity and recognize tumors with
reduced expression of major histocompatibility complex (MHC) class I. Natural killer
group 2 member D (NKG2D) is an activation receptor in NK cells, whose ligands are MHC
class I-related chains A and B (MICA/B). The tumor expression of MICA/B induced by
BRAF and RAS has been observed in ATC and is responsible for the antitumor effects of
NK cells [
6
]. Extracellular vehicles (EVs) may contribute to the cytotoxicity of NK cells
in TC [
7
]. The infiltration of NK cells is markedly higher in PTC than in benign thyroid
nodules [
8
], and circulating NK cells are notably increased in patients with advanced TC
compared to healthy individuals [
9
]. In ATC, enriched CD56bright CD16
−
/low NK cells
express high levels of exhaustion markers, including programmed cell death-1 (PD-1),
T-cell immunoglobulin, and mucin domain 3 (TIM3), with decreased levels of NKp44,
NKp30, and NKG2D [
9
–
11
], suggesting that the function of these NK cells is inhibited. The
cytotoxicity of these NK cells is restored by PD-1 and TIM3 blockade or by neutralization
of prostaglandin E2. Collectively, NK cells infiltrate TC through MICA/B, followed by NK
cell exhaustion, and the dysfunction of these cells is replenished by immune checkpoint
inhibitors (ICIs) or cyclooxygenase (COX) inhibitors.
Interactions between antigen-presenting cells and T cells are indispensable to activate
acquired immunity. Regarding antigen-presenting cells, S100+ (mature and immature),
CD1a
+
(immature), and CD83
+
(mature) dendritic cells (DCs) have been detected in human
PTC samples [
12
]. Chemokine receptor-6+ DC-SIGN
+
DCs also infiltrate PTC but are scarce
in FTC [
13
]. DC infiltration is markedly reduced in poorly differentiated TC and ATC [
14
].
Although Cunha et al. reported that CD8
+
T-cell infiltration correlates with a favorable
prognosis in patients with DTC [
15
], the same group has shown that the combination of
CD8
+
cells and COX-2 overexpression is associated with the risk of recurrent DTC [
16
].
In addition to COX-2, which is considered an immunosuppressive factor that produces
prostaglandin E2, the relationship between CD8
+
T cells and TC remains to be elucidated.
Similarly, the antitumor effects of B cells in TC remain unknown. Few studies have revealed
that the infiltration of B cells into tumors that form tertiary lymphoid tissue is associated
with a favorable prognosis in PTC [17,18]. BRAF mutations in tumors may be responsible
for the reduced infiltration of B cells.
2.2. Immune-Suppressing Cells
Tumor-associated macrophages (TAM) and M2 macrophages suppress the expression
of other immune cells. In PTC, increased TAM density is associated with extrathyroid
invasion, lymph node metastasis, and tumor progression [
19
–
21
]. Additionally, PTC-
derived TAM promotes tumor invasion and metastasis by producing CXCL8 [
20
]. ATC
has a higher M2 macrophage (CD163
+
) infiltration than other types of cancer [
22
]. In
addition to TAM, myeloid-derived suppressor cells (MDSCs) inhibit antitumor immune
cells. The number of circulating MDSCs is associated with the aggressive characteristics
of DTC [
23
], and the circulating MDSCs in patients with ATC are significantly higher
than those in healthy individuals [
24
]. Mast cells are associated with angiogenesis [
25
],
lymphangiogenesis [
26
], and tumor progression [
27
–
29
]. Melillo et al. revealed that the
mast cell density in PTC was higher than that in normal tissue, and that was related to
extra-thyroid tumor invasion [
30
]. A higher mast cell density was also found in FTC
than in adenomas and was related to extracapsular extension [
31
]. Neutrophils support
tumor growth through neutrophil extracellular traps. A high neutrophil/lymphocyte
ratio is correlated with a large tumor size and a high risk of recurrence in patients with

Vaccines 2024,12, 45 3 of 17
TC [
32
,
33
]. French et al. reported that the frequency of regulatory T cells (Tregs) positively
correlated with lymph node metastasis in PTC [
34
]. They also reported that Tregs were
enriched in tumor-involved lymph nodes and that their frequency was associated with
PTC recurrence [
35
]. Liu et al. also found that a high percentage of Tregs in both peripheral
blood and tumor tissue correlated with extrathyroid invasion and lymph node metastasis
in PTC [
36
]. In addition to Tregs, regulatory B cells that inhibit IFN-
γ
-production from
CD4+and CD8+T cells through IL-10 have been observed in DTC [37].
Collectively, immune-suppressive cells are frequently observed in advanced TC, and
the activation of antitumor immune cells by overwhelming these suppressive cells may
pave the way for establishing novel immunotherapies against TC (Figure 1).
Vaccines 2024, 12, x FOR PEER REVIEW 3 of 18
through neutrophil extracellular traps. A high neutrophil/lymphocyte ratio is correlated
with a large tumor size and a high risk of recurrence in patients with TC [32,33]. French
et al. reported that the frequency of regulatory T cells (Tregs) positively correlated with
lymph node metastasis in PTC [34]. They also reported that Tregs were enriched in tumor-
involved lymph nodes and that their frequency was associated with PTC recurrence [35].
Liu et al. also found that a high percentage of Tregs in both peripheral blood and tumor
tissue correlated with extrathyroid invasion and lymph node metastasis in PTC [36]. In
addition to Tregs, regulatory B cells that inhibit IFN-γ-production from CD4+ and CD8+ T
cells through IL-10 have been observed in DTC [37].
Collectively, immune-suppressive cells are frequently observed in advanced TC, and
the activation of antitumor immune cells by overwhelming these suppressive cells may
pave the way for establishing novel immunotherapies against TC (Figure 1).
Figure 1. Interaction of immune-suppressing cells with thyroid cancer.
Immune-suppressing cells, including macrophages, MDSCs, neutrophils, Tregs, and
mast cells, are frequently observed in thyroid cancer. Immune-suppressing cells and tu-
mor cells interact with each other via chemokines and cytokines.
3. Immunosuppression by TC
In addition to immune-suppressing cells, the tumor itself can suppress and escape
antitumor immune cells, leading to tumor progression. In TC, immune escape occurs
through several mechanisms. The decreased expression of MHC class I molecules and β2-
microglobulin, a component of MHC, in TC cells supports the evasion of cytotoxic T cell
activity by suppressing antigen presentation [38,39]. The cell signaling pathway is partly
responsible for diminished antigen presentation in TC. RET is a receptor tyrosine kinase
that regulates cell proliferation and survival through mitogen-activated protein kinase
(MAPK) and phosphatidylinositol-3 kinase (PI3K)/Akt in sporadic MTC and some PTCs
[40–42]. Aberrant activation of RET contributes to the reduced expression of MHC class II
[43]. In addition to suppressing antigen presentation, TC upregulates negative immune
checkpoint molecules, such as programmed cell death ligand-1 (PD-L1) and programmed
cell death ligand-2, which suppress the activation of T and NK cells through PD-1 [44,45].
Several studies have reported that BRAF V600E mutation correlated with high levels of
PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [46–51]. The expression
of these immune checkpoints inhibits CD8+ cytotoxic T cells and increases the number of
FoxP3+ Tregs and M2 macrophages. Other negative immune checkpoints, including
VISTA, B7H3, TIM3, TIGIT, LAG3, PDCD1, and PVR, have also been found in PTC, MTC,
and ATC tissues [5,52–54].
Thyroid
cancer T cell
B cell
MICA/B
Antigen-presenting
ATC:high
NK cell
NKG2D
PTC:high
MHC
DC
CCR-6+
DC-SIGN+
PTC:high
FTC:low
ATC:low
Innate immunity Acquired immunity
Killing
NK cell
(exhausted)
NKG2D
ATC:low
PD-1
ATC:high
TIM3
Killing
PD-1 blockade
TIM3 blockade
PGE2 neutralization
COX inhibition
Antigen
Thyroglobulin
TSH receptor
Calcitonin(FTC)
CEA(MTC)
ICAM-1
MAGE-A, 3, A3, C1
G antigen
Cancer testis
antigen 1B
Neoantigen
BRAF V600E
KRAS
PI3K
Figure 1. Interaction of immune-suppressing cells with thyroid cancer.
Immune-suppressing cells, including macrophages, MDSCs, neutrophils, Tregs, and
mast cells, are frequently observed in thyroid cancer. Immune-suppressing cells and tumor
cells interact with each other via chemokines and cytokines.
3. Immunosuppression by TC
In addition to immune-suppressing cells, the tumor itself can suppress and escape
antitumor immune cells, leading to tumor progression. In TC, immune escape occurs
through several mechanisms. The decreased expression of MHC class I molecules and
β
2-microglobulin, a component of MHC, in TC cells supports the evasion of cytotoxic T cell
activity by suppressing antigen presentation [
38
,
39
]. The cell signaling pathway is partly
responsible for diminished antigen presentation in TC. RET is a receptor tyrosine kinase that
regulates cell proliferation and survival through mitogen-activated protein kinase (MAPK)
and phosphatidylinositol-3 kinase (PI3K)/Akt in sporadic MTC and some PTCs [
40
–
42
].
Aberrant activation of RET contributes to the reduced expression of MHC class II [
43
]. In
addition to suppressing antigen presentation, TC upregulates negative immune checkpoint
molecules, such as programmed cell death ligand-1 (PD-L1) and programmed cell death
ligand-2, which suppress the activation of T and NK cells through PD-1 [
44
,
45
]. Several
studies have reported that BRAF V600E mutation correlated with high levels of PD-L1 and
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [
46
–
51
]. The expression of these
immune checkpoints inhibits CD8
+
cytotoxic T cells and increases the number of FoxP3
+
Tregs and M2 macrophages. Other negative immune checkpoints, including VISTA, B7H3,
TIM3, TIGIT, LAG3, PDCD1, and PVR, have also been found in PTC, MTC, and ATC
tissues [5,52–54].
Soluble mediators, including cytokines, chemokines, angiogenic factors, and metabolic
enzymes, can diminish the anticancer effects of immune cells in TC. Both immune-suppressing
and TC cells produce immune-suppressing cytokines that play crucial roles in TC devel-

Vaccines 2024,12, 45 4 of 17
opment [
27
]. Interleukin (IL)-6 contributes to tumor cell proliferation, survival, invasion,
and metastasis through MDSCs accumulation and activation. IL-6 is highly expressed in
DTC and associated with tumor invasiveness [
55
]. ATC cells produce IL-6, which promotes
tumor progression through M2 macrophage activation through signal transducers and
activators of transcription (STAT) 3 signaling [
56
,
57
]. IL-10, an anti-inflammatory and
immunosuppressive cytokine that contributes to immune escape by downregulating MHC
class I on the cell surface, is produced by TAMs and TC cells. IL-10 expression in TC is
associated with extrathyroid invasion and a large tumor size [
58
]. MDSCs numbers are high
in patients with ATC and MTC and are associated with high IL-10 production [
24
]. Todaro
et al. found that TC cells produce IL-4 and IL-10 that promote resistance to chemotherapy
by upregulating Bcl-xL and Bcl-2, which suppress apoptosis [
59
,
60
]. Prostaglandin E2 is
produced through COX2 in ATC [
11
]. Prostaglandin E2 suppresses the maturation and
antitumor activity of NK cells against TC. Transforming growth factor (TGF)-
β
signaling
plays different roles in cancer cells and normal cells. Exerting antimitogenic effects in
normal thyroid follicular cells, TGF-
β
promotes cancer development, migration, invasion,
and induction of epithelial–mesenchymal transition (EMT) [61,62].
Chemokines play a role in tumor growth and angiogenesis. In addition to cytokines,
thyroid cells release CXC chemokines, including CXCL1, CXCL8, CXCL9, CXCL10, and
CXCL11 [
63
]. PTC and ATC cells produce high levels of CXCL1, CXCL8, and CXCL10 [
64
,
65
].
The expression of CXCL12 was higher in PTC than in normal tissues and is associated
with lymph node metastasis [
66
]. CXCR4 and CXCR7, both CXCL12 receptors, are highly
expressed in PTC and are associated with tumor progression [
67
,
68
]. CXCL12-CXCR4
axis promotes migration, invasion, and EMT in human PTC cells through activation of
the NF-
κ
B signaling [
68
]. CXCR4 and CXCR7 expression is associated with large tumor
size, advanced TNM staging, and short overall and recurrence-free survival in FTC [
69
].
Microarray analysis has revealed that CXCL8 expression is higher in ATC tissues than
in normal thyroid tissues [
70
]. TAM may facilitate PTC metastasis through paracrine
interactions with CXCL8 and CXCR1/2 [
20
]. CXCL8 and vascular endothelial growth factor
(VEGF)-A secretion from poorly DTC is induced by thyroid-stimulating hormone (TSH)
signaling, which regulates tumor angiogenesis, macrophage infiltration, and enhanced
tumor growth [
71
]. CXCL8/CXCR1, CXCL1/CXCR2, and CXCL10/CXCR3 produced
by mast cells promote TC cell proliferation, survival, invasion, EMT, and stemness [
72
].
Regarding the interaction between cytokines and chemokines, IFN-
γ
and TNF-
α
induce
CXCL10/IP-10 production in human PTC and ATC cells [64,73].
VEGF is a key mediator of angiogenesis and an inducer of Tregs in the cancer mi-
croenvironment [
74
]. Both PTC and ATC express VEGF [
75
,
76
]. VEGF from TC cells
induces neovascularization and suppresses DCs [
77
]. TC cells release VEGF-A, which
recruits mast cells and correlates with the invasive tumor phenotype [
30
]. VEGF expression
is significantly correlated with BRAF V600E expression in PTC with extrathyroid inva-
sion [
78
]. VEGF-A, colony-stimulating factor 1, and CCL2 can attract monocytes to the
tumor microenvironment and differentiate them into TAM [
79
]. Collectively, VEGF plays a
significant role not only in vascularization but also in immune modulation.
Amino acid metabolites are necessary for the survival of antitumor immune cells. In
addition to M2 macrophages, TC cells can produce metabolic enzymes such as indoleamine
2,3-dioxygenase 1 (IDO1) or arginase-1 (ARG1), which reduce the amino acids necessary for
immune cells. In PTC, IDO1 mRNA expression is associated with tumor IDO1 immunos-
taining intensity and FoxP3
+
Treg density [
80
]. IDO1 mRNA expression is higher in patients
with ATC than in patients with PTC or MDC. TC secretes IDO, ARG-1, and TGF-
β
, which
inhibit the expression of NK cell surface-activation receptors and decrease the number
and quality of NK cells [
81
]. A low intratumoral CD8
+
/Foxp3
+
ratio was observed in
patients with increased expression of IDO, ARG-1, and PD-L1, which is related to the BRAF
V600E mutation [
47
]. Taken together, these results indicate that TC can directly suppress
antitumor cells through numerous pathways, including negative immune checkpoints and
soluble factors.

Vaccines 2024,12, 45 5 of 17
4. The Immunological Targets and Immunization in TC
4.1. The Expression of Programmed Cell Death Ligand-1
Negative immune checkpoints expressed on the surface of immune-suppressing or
tumor cells inhibit the immune system, leading to immune tolerance. The interaction
between PD-L1 and PD-1 suppresses the effector functions of cytotoxic T cells and NK cells.
PD-1 inhibitors have shown clinical efficacy in other cancer types, and the expression of
PD-L1 is considered a favorable biomarker for PD-1 inhibitors [82,83].
Several studies have examined PD-L1 expression by immunostaining in TC cells. In
DTC, the positivity of PD-L1 varied among studies. Although two studies focusing on
PTC reported low PD-L1 positivity rates, ranging from 6.1 to 10.1% [
53
,
84
], other studies
reported higher PD-L1 positivity rates, ranging from 0.3 to 87% [
47
,
85
,
86
]. It should be
noted that the expression of PD-L1 is significantly higher in aggressive PTC than in non-
aggressive PTC [
85
]. Two studies on FTC reported PD-L1 positivity rates of 7.6% and 59.7%,
respectively [
84
,
87
]. PD-L1 expression is relatively low, with positivity rates ranging from
12.5 to 14.4% in MTC [
88
,
89
]. In ATC, the expression of PD-L1 is relatively high, ranging
from 60 to 81.3% [
53
,
86
,
90
,
91
]. A direct comparison between histological types has shown
that higher expression of PD-L1 is observed in ATC than in DTC [
84
,
86
]. PD-L1 is diffusely
expressed in ATC, whereas it is localized in PTC [
84
]. Collectively, PD-L1 may be highly
expressed in aggressive PTC and ATC, for which additional treatment is necessary. Further
studies to evaluate the selection of antibodies to detect PD-L1, measurement methods such as the
combined positive score [92] and cutoff values are required for the accurate detection of PD-L1.
4.2. The Candidates in TC-Specific Immunotherapy
The drawback of the PD-1 blockade is the non-specific activation of T cells, most of
which are irrelevant to tumors and compete with anti-tumor T cells. Chimeric antigen
receptor (CAR)-T therapy and cancer vaccines are promising cancer-specific immunother-
apy approaches [
93
,
94
]. These immunotherapies are designed to target specific proteins
expressed in the tumor cells. Thus, it is crucial to identify optimal targets that are predomi-
nantly expressed in tumors but not in normal cells [94].
Most TC and normal thyroid tissues express thyroid-specific proteins, such as thy-
roglobulin (TG) and TSH receptors. TG is strongly expressed in all normal thyroid samples
but not in other normal tissues [
95
]. Patients with recurrent TC generally undergo total
thyroidectomy, making these proteins ideal targets for cancer-specific immunotherapy [
96
].
The positivity rates for TG in the PTC, FTC, and ATC groups are 98.1%, 95.2%, and 7.5%,
respectively [
96
,
97
]. In patients with DTC, the positivity rate of TSH receptors ranges
from 68 to 90.8% [
96
,
98
,
99
], and high expression of TSH receptors in lymph node metas-
tases is associated with poor prognosis [
98
,
99
]. Peripheral TG-reactive CD8
+
T cells have
been observed in patients with PTC [
96
,
97
,
100
], and TSH receptor-targeted CAR-T cell
therapy has shown significant antitumor effects without apparent toxicity
in vivo
[
96
]. In
FTC, calcitonin may be a target for inducing antitumor CD8
+
T cells using a DC-based
vaccine [101].
Although thyroid-specific proteins are potential targets for immunotherapy in DTC,
their expression is reduced in ATC [
95
,
102
]. Tumor-associated antigens (TAAs) are proteins
involved in tumor growth that are expressed at low levels in normal tissues [
94
]. Inter-
cellular adhesion molecule-1 (ICAM-1) is a well-studied TAA used to treat TC. ICAM-1
is a member of the immunoglobulin superfamily that mediates cell–cell interactions, and
its expression is faintly detectable in epithelial cells and normal thyroid tissues under
non-inflammatory conditions. The reported positivity rate of ICAM-1 by immunostain-
ing is 85.6% in patients with PTC [
103
]. Another study showed that 100% of patients
with ATC were positive for ICAM-1, and the staining levels were higher in ATC than in
PTC [
104
]. ICAM-1 expression correlates with poor prognosis and metastasis in TC [
105
].
The antitumor activity of ICAM-1-targeted immunotherapy with CAR-T cells and mono-
clonal antibody-based treatment has been reported [
104
–
107
]. ICAM-1-targeted CAR-T cell
therapy has shown robust antitumor effects in PTC and ATC models [104–107].

Vaccines 2024,12, 45 6 of 17
Carcinoembryonic antigen (CEA) belongs to the immunoglobulin superfamily. CEA
is mainly expressed in MTC and gastrointestinal adenocarcinoma and is associated with
metastasis. Most patients with MTC express CEA, ranging from 77 to 100% [
108
–
110
].
Clinical trials using DCs- and yeast-based vaccines against CEA have been conducted
for several types of cancers, including MTC [
111
–
113
]. Cancer-testis antigens are TAAs
expressed only in the testis and cancer, and their expression is associated with tumor
progression [
94
]. Among cancer-testis antigens, the positivity rate for melanoma-associated
antigen (MAGE)-A3 is 94.87% in patients with DTC [
114
]. Milkovic et al. described that the
positivity rates of MAGE-3 were 80% and 29% in PTC and FTC, respectively [
115
]. In TC,
including poorly differentiated TC and ATC, the positivity for cancer-testis antigens is as
follows: MAGE-A, 61.8%; MAGE-C1, 57.1%; G antigen, 66.7%; and cancer-testis antigen
1 B, 14.4% [116].
Tumor-specific antigens (TSAs) are highly immunogenic antigens expressed only
in tumor cells. Neoantigens are TSAs produced by tumor-specific mutations and are
considered suitable targets for cancer vaccines [
117
]. Although little is known regarding
neoantigens in TC, several studies have indicated that abundant neoantigens are expressed
in ATCs compared to other types of TC [
118
,
119
]. Several molecular pathways, including
the MAPK and PI3K/Akt pathways, have been suggested to play roles in the development
of TC [
120
]. Mutations in molecules within these signaling pathways, including BRAF,
RAS, RET, and PTEN, have been detected in various TC types and are associated with
disease progression and poor prognosis. BRAF is the most frequently mutated protein, and
mutations are observed in approximately 40–45% of TC cases. The most common BRAF
mutation is the V600E transversion, with some studies suggesting that 36% of patients with
PTC harbor this mutation [
121
–
123
]. The BRAF V600E mutation activates MAPK signaling
and is associated with poor outcomes and high recurrence rates [
121
,
124
]. Furthermore,
10–50% of patients with ATC carry the BRAF V600E mutation, which is associated with a
poor prognosis [
86
,
125
–
127
]. Mutations or overexpression of the RAS gene family, including
HRAS,KRAS, and NRAS, are observed in 20–30% of TC. RAS and RAF mutations contribute
to tumor growth and survival by activating downstream signaling pathways such as
MAPK/ERK and PI3K/Akt [
128
]. As neoantigens have been found in BRAF V600E, KRAS,
and PI3K [
129
,
130
], these mutated signaling proteins are targets of TSAs in tumor-specific
immunotherapy. Collectively, the activation of antigen-specific T cells in addition to NK
cells is a promising strategy to treat thyroid cancer (Figure 2).
Vaccines 2024, 12, x FOR PEER REVIEW 7 of 18
Figure 2. Antitumor immunity in thyroid cancer.
Both innate and acquired immune cells may aack thyroid cancer cells. The anti-
tumor ability of exhausted NK cells in ATC is recovered by immune checkpoint blockade
or COX inhibitor. Thyroid cancer expresses several tumor-associated antigens and neoan-
tigens that can be recognized by antitumor T cells.
4.3. Immunization against TC
Active immunization (cancer vaccine) and ex vivo proliferation of antigen-specic T
cells followed by adoptive cell transfer (ACT) are promising approaches to potentiate anti-
TC T cells using the candidate antigens as mentioned above (e.g., TG and CEA). Although
the antitumor eect of vaccination has not been thoughtfully examined in TC, this ap-
proach has achieved clinical benets in several types of cancer. In melanoma, vaccinations
or ACTs are eective to suppress tumors. Rahdan et al. have shown preventive ecacy of
peptide vaccine in preclinical models [131]. The combination of peptides with appropriate
adjuvants such as poly-IC and CD40 could induce robust antitumor responses in a mela-
noma model [132]. In castration-resistant prostate cancer, personalized peptide vaccine
has achieved clinical responses in a phase 2 study [133]. In TC, a DC-based vaccine using
an autologous tumor lysate as an antigen [134] and a yeast-based vaccine targeting CEA
[135] have shown promising results. Further trials are necessary to conrm that immun-
ization can induce antitumor responses in TC as well as melanoma and prostate cancer.
5. Experimental and Clinical Immunotherapy against TC
Owing to the challenges in establishing preclinical models, only a few studies on im-
munotherapy targeting TC in immunocompetent mouse models have been reported.
Anti-PD-1 blockade has shown mild antitumor eects in a transgenic mouse model of
spontaneous PTC [136]. In other studies, anti-PD-1 or -PD-L1 therapy had no eect on
orthotopic murine ATC [51,137,138] or on a transgenic mouse model of DTC progressing
to ATC [139]. Despite the weak ecacy of ICI monotherapy, combination therapy with
ICIs and molecule-targeted therapies is promising for preclinical studies. Lenvatinib (an
oral multi-TKI against VEGFR1-3, broblast growth factor receptor (FGFR)1-4, platelet-
derived growth factor receptor alpha, RET, and c-kit) increases CD8+ T cell and cytotoxic
CD4+ T cell inltration with decreased polymorphonuclear MDSCs, resulting in signi-
cant antitumor eects when combined with anti-PD-1 or PD-L1 therapy against ATC
Figure 2. Antitumor immunity in thyroid cancer.

Vaccines 2024,12, 45 7 of 17
Both innate and acquired immune cells may attack thyroid cancer cells. The antitumor
ability of exhausted NK cells in ATC is recovered by immune checkpoint blockade or COX
inhibitor. Thyroid cancer expresses several tumor-associated antigens and neoantigens that
can be recognized by antitumor T cells.
4.3. Immunization against TC
Active immunization (cancer vaccine) and ex vivo proliferation of antigen-specific T
cells followed by adoptive cell transfer (ACT) are promising approaches to potentiate anti-
TC T cells using the candidate antigens as mentioned above (e.g., TG and CEA). Although
the antitumor effect of vaccination has not been thoughtfully examined in TC, this ap-
proach has achieved clinical benefits in several types of cancer. In melanoma, vaccinations
or ACTs are effective to suppress tumors. Rahdan et al. have shown preventive efficacy
of peptide vaccine in preclinical models [
131
]. The combination of peptides with appro-
priate adjuvants such as poly-IC and CD40 could induce robust antitumor responses in a
melanoma model [
132
]. In castration-resistant prostate cancer, personalized peptide vaccine
has achieved clinical responses in a phase 2 study [
133
]. In TC, a DC-based vaccine using an
autologous tumor lysate as an antigen [
134
] and a yeast-based vaccine targeting CEA [
135
]
have shown promising results. Further trials are necessary to confirm that immunization
can induce antitumor responses in TC as well as melanoma and prostate cancer.
5. Experimental and Clinical Immunotherapy against TC
Owing to the challenges in establishing preclinical models, only a few studies on
immunotherapy targeting TC in immunocompetent mouse models have been reported.
Anti-PD-1 blockade has shown mild antitumor effects in a transgenic mouse model of
spontaneous PTC [
136
]. In other studies, anti-PD-1 or -PD-L1 therapy had no effect on
orthotopic murine ATC [
51
,
137
,
138
] or on a transgenic mouse model of DTC progressing
to ATC [
139
]. Despite the weak efficacy of ICI monotherapy, combination therapy with
ICIs and molecule-targeted therapies is promising for preclinical studies. Lenvatinib (an
oral multi-TKI against VEGFR1-3, fibroblast growth factor receptor (FGFR)1-4, platelet-
derived growth factor receptor alpha, RET, and c-kit) increases CD8
+
T cell and cytotoxic
CD4
+
T cell infiltration with decreased polymorphonuclear MDSCs, resulting in significant
antitumor effects when combined with anti-PD-1 or PD-L1 therapy against ATC [
138
,
139
].
Combination therapy with BRAF inhibitors and ICIs dramatically reduces tumor growth in
PTC- and ATC-bearing mice, with increased tumor-infiltrating CD8
+
T cells, NK cells, or
CD4
+
T cells subsequent to the upregulation of tumoral MHC class II expression through
class II major histocompatibility complex transactivator [
51
,
136
,
137
]. Regarding tumor-
specific immunotherapy, ICIs enhanced the antitumor effect of ICAM1-targeting CAR-
T cell therapy in a xenograft ATC model [
106
]. These preclinical results suggest that
immunotherapy is a promising therapeutic strategy for TC.
Clinical evidence for the efficacy of ICIs against TC has gradually emerged. In a
Phase Ib clinical trial (KEYNOTE-028), 22 patients with standard treatment-resistant PTC or
FTC and high PD-L1 expression were evaluated for safety and efficacy of pembrolizumab,
an anti-PD-1 antibody [
140
]. The median progression-free survival was 7 months with
a favorable safety profile, and two patients exhibited a partial response [
140
]. As a part
of phase I/II spartalizumab study against advanced solid tumor, 42 patients with locally
advanced and/or metastatic ATC were treated by PD-1 blockade in the phase II cohort [
141
].
The response rate was 19% (three patients with complete response and five patients with
partial response). Notably, patients with PD-L1–positive tumors (PD-L1 > 50%) had high
response rates (8/28; 29%), whereas patients with PD-L1-negative tumors had no responses
(0/12; 0%) [
141
]. In another study, pembrolizumab or nivolumab showed 16% response
rates with two partial response, and one-year survival rate was 38% in 13 patients with
locally advanced or metastatic unresectable ATC [
142
]. As well as other types of tumors,
such as melanoma, lung cancer, and head and neck squamous carcinoma [
143
,
144
], these
results indicate that PD-1 inhibitors are effective in some patients with DTC or ATC, but the

Vaccines 2024,12, 45 8 of 17
number of responders is limited. Another type of ICIs, the CTLA-4 inhibitor, is considered
to activate T-cell priming. Although it is difficult to interpret the results of a phase I
trial, three patients with TC who received CTLA-4 inhibitor monotherapy did not show
significant antitumor effects [145].
Due to the unsatisfactory results of monotherapy in clinical trials, combined ap-
proaches using ICIs have been explored. Xing et al. reported that patients with PD-L1
positive ATC achieved a complete response to a combination of radiotherapy and an
anti-PD-1 antibody (tislelizumab) [
146
]. Although chemotherapy combined with ICIs has
shown favorable results in some cancer types, a phase II clinical trial of pembrolizumab with
chemoradiotherapy (docetaxel/doxorubicin) showed no clinical benefit in three patients
with ATC [
147
]. To examine the use of ICIs in TC, an ongoing clinical trial is evaluating
the clinical benefits of combining ipilimumab and nivolumab in radioiodine-refractory TC
(NCT03246958).
Small-molecule-targeted therapy synergizes with ICIs by modulating the immune
microenvironment. Similar to preclinical studies, clinical cases have shown favorable
responses to ICIs combined with targeted therapies, including lenvatinib [
148
–
152
]. These
studies showed that the combination therapy against ATC achieved 60–66% overall re-
sponse rates, and the median overall survival was 8.3–18.5 months [
148
,
149
]. As sev-
eral prospective studies have reported that the monotherapy of lenvatinib against ATC
showed response rates of 3–24%, and the median overall survival ranged from 3.2 to
10.6 months [
153
–
156
], this combined approach would be a hopeful treatment. Other multi-
TKIs, such as cabozantinib and anlotinib, have also shown synergy with anti-PD-1 therapy,
leading to long-term survival in patients with ATC [
157
,
158
]. Moreover, ICIs combined
with apatinib, a TKI that selectively inhibits VEGFR-2, achieved a partial response in a
patient with radioiodine-refractory DTC [
159
]. Dabrafenib and trametinib (BRAF and MEK
inhibitors) have shown a complete response against ATC with ICIs [
160
,
161
]. To date, the
inhibition of MEK, FGFR, and VEGFR has been shown to modulate immunity by upreg-
ulating MHC expression and activating T cells in other tumor types [
162
–
164
]. As these
molecules are widely expressed in TC, a more detailed immunological analysis of these
proteins in TC is required to integrate basic and translational studies into clinical practice.
6. Conclusions and Future Directions
In this review, we summarize current findings on the immune microenvironment,
immunosuppression, immunological targets, and immunotherapy in advanced TC. Ac-
cording to the immune surveillance hypothesis, aggressive tumors often escape antitumor
immunity. Tumor MHC expression and CD8
+
T cell and NK cell infiltration are suppressed
in advanced TC [
15
,
165
]. Although TAM, MDSCs, Tregs, negative immune checkpoints,
cytokines/chemokines, VEGF, and IDO-1 are hypothesized to suppress antitumor T cells in
aggressive TC, ICIs and VEGF are the only actionable targets to date. As molecule-targeted
therapies such as MAPK inhibitors upregulate the cytotoxicity of immune cells [
6
], the
combination of ICIs and molecule-targeted therapy is a promising approach for activat-
ing antitumor immunity (Figure 3). Although the combination of PD-1 blockades and
lenvatinib has shown promising clinical responses as a first-line therapy for advanced or
recurrent endometrial cancer [
166
], LEAP-08 and LEAP-10 did not show clinical benefits in
lung cancer and head and neck cancer, respectively. This combination should also be tested
for TC, for which lenvatinib has already been clinically approved. Further prospective
clinical trials combining molecular targeted therapy with ICIs are required to treat TC.
Despite the release of T cells from negative immune checkpoints activating antitumor
T cells, only a limited number of patients respond to tumor-nonspecific immunotherapy.
Patients with enriched inflammatory response pathways and high levels of immune cell
infiltration may respond to ICIs in TC [
167
]; however, particular biomarkers to identify
ICI responders are yet to be identified. PD-L1 expression in the stroma or the detection
of tumor-reactive T cells using a TAA-derived epitope would be useful for determining
responders to ICIs. Further treatment options should be established for most patients with

Vaccines 2024,12, 45 9 of 17
TC who cannot respond to ICIs. As tumor-specific immunotherapy has exhibited signifi-
cant antitumor effects in preclinical PTC and ATC models [
105
,
106
], further translational
research is necessary to confirm the clinical responses to this novel mode of immunotherapy
in advanced TC.
Vaccines 2024, 12, x FOR PEER REVIEW 9 of 18
6. Conclusions and Future Directions
In this review, we summarize current ndings on the immune microenvironment,
immunosuppression, immunological targets, and immunotherapy in advanced TC. Ac-
cording to the immune surveillance hypothesis, aggressive tumors often escape antitumor
immunity. Tumor MHC expression and CD8+ T cell and NK cell inltration are sup-
pressed in advanced TC [15,165]. Although TAM, MDSCs, Tregs, negative immune check-
points, cytokines/chemokines, VEGF, and IDO-1 are hypothesized to suppress antitumor
T cells in aggressive TC, ICIs and VEGF are the only actionable targets to date. As mole-
cule-targeted therapies such as MAPK inhibitors upregulate the cytotoxicity of immune
cells [6], the combination of ICIs and molecule-targeted therapy is a promising approach
for activating antitumor immunity (Figure 3). Although the combination of PD-1 block-
ades and lenvatinib has shown promising clinical responses as a rst-line therapy for ad-
vanced or recurrent endometrial cancer [166], LEAP-08 and LEAP-10 did not show clinical
benets in lung cancer and head and neck cancer, respectively. This combination should
also be tested for TC, for which lenvatinib has already been clinically approved. Further
prospective clinical trials combining molecular targeted therapy with ICIs are required to
treat TC.
Despite the release of T cells from negative immune checkpoints activating antitumor
T cells, only a limited number of patients respond to tumor-nonspecic immunotherapy.
Patients with enriched inammatory response pathways and high levels of immune cell
inltration may respond to ICIs in TC [167]; however, particular biomarkers to identify
ICI responders are yet to be identied. PD-L1 expression in the stroma or the detection of
tumor-reactive T cells using a TAA-derived epitope would be useful for determining re-
sponders to ICIs. Further treatment options should be established for most patients with
TC who cannot respond to ICIs. As tumor-specic immunotherapy has exhibited signi-
cant antitumor eects in preclinical PTC and ATC models [105,106], further translational
research is necessary to conrm the clinical responses to this novel mode of immunother-
apy in advanced TC.
Figure 3. Immunotherapeutic Targets for Thyroid Cancer.
Various molecules and pathways, including decreased MHC and increased negative
immune checkpoints such as PDL1, contribute to immune escape of thyroid cancer. The
inhibitors of signaling pathways (e.g., EGFR, RET, and VEGFR) can be used as immuno-
modulators. The antigens derived from thyroid cancer may be a source of cancer vaccines
and CAR-T therapy. TAA: tumor-associated antigen.
M AP K
pathw ay
PI3K/A KT
pathw ay
Figure 3. Immunotherapeutic Targets for Thyroid Cancer.
Various molecules and pathways, including decreased MHC and increased negative
immune checkpoints such as PDL1, contribute to immune escape of thyroid cancer. The
inhibitors of signaling pathways (e.g., EGFR, RET, and VEGFR) can be used as immunomod-
ulators. The antigens derived from thyroid cancer may be a source of cancer vaccines and
CAR-T therapy. TAA: tumor-associated antigen.
Author Contributions: H.K., M.K., R.W., R.S., T.I. and T.K. contributed to writing the manuscript.
H.K., M.K., M.T. and T.K. designed the study. All authors have read and agreed to the published
version of the manuscript.
Funding: This work was supported by JSPS KAKENHI Grant Number 22K09659, 23K08977, and 23K08929.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Acknowledgments: The figures were created with BioRender.com (17 November 2023). The au-
thors thank Hajime Kamada (Hokuto Social Medical Corporation) for his excellent suggestions for
the manuscript.
Conflicts of Interest: No potential conflicts of interest were disclosed.
Abbreviations
ARG1 Arginase-1
ACT Adoptive cell transfer
ATC Anaplastic thyroid cancer
CAR Chimeric antigen receptor
CEA Carcinoembryonic antigen
COX Cyclooxygenase
CTLA-4 Cytotoxic T-Lymphocyte-Associated Protein 4
DCs Dendritic cells
DTC Differentiated thyroid cancer
EMT Epithelial–mesenchymal transition
FGFR Fibroblast growth factor receptor
FTC Follicular thyroid cancer

Vaccines 2024,12, 45 10 of 17
ICAM-1 Intercellular adhesion molecule-1
ICIs Immune checkpoint inhibitors
IDO1 Indoleamine 2,3-dioxygenase 1
IL Interleukin
MAGE Melanoma-associated antigen
MAPK Mitogen-activated protein kinase
MDSCs Myeloid-derived suppressor cells
MHC Major histocompatibility complex
MICA/B Major histocompatibility complex class I-related chains A and B
MTC Medullary thyroid cancer
NK cells Natural killer cells
NKG2D Natural killer group 2 member D
NLR Neutrophil to lymphocyte ratio
OS Overall survival
PD-1 Programmed cell death-1
PD-L1 Programmed cell death ligand-1
PI3K Phosphatidylinositol-3 kinase
PTC Papillary thyroid cancer
RAI Radioiodine therapy
STAT Signal transducer and activator of transcription
TAAs Tumor-associate antigens
TAM Tumor-associated macrophages
TC Thyroid cancer
TG Thyroglobulin
TGF Transforming growth factor
TIM3 T cell immunoglobulin and mucin domain 3
TKIs Tyrosine kinase inhibitors
Tregs Regulatory T cells
TSAs Tumor-specific antigens
TSH Thyroid stimulating hormone
VEGF Vascular endothelial growth factor
References
1.
Bao, W.; Zi, H.; Yuan, Q.; Li, L.; Deng, T. Global burden of thyroid cancer and its attributable risk factors in 204 countries and
territories from 1990 to 2019. Thorac. Cancer 2021,12, 2494–2503. [CrossRef] [PubMed]
2.
Ruel, E.; Thomas, S.; Dinan, M.; Perkins, J.M.; Roman, S.A.; Sosa, J.A. Adjuvant radioactive iodine therapy is associated with
improved survival for patients with intermediate-risk papillary thyroid cancer. J. Clin. Endocrinol. Metab. 2015,100, 1529–1536.
[CrossRef] [PubMed]
3.
TuttleMD, R.M.; Ahuja, S.; Avram, A.M.; Bernet, V.J.; Bourguet, P.; Daniels, G.H.; Dillehay, G.; Draganescu, C.; Flux, G.; Fuehrer,
D.; et al. Controversies, Consensus, and Collaboration in the Use of
131
I Therapy in Differentiated Thyroid Cancer: A Joint
Statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear
Medicine and Molecular Imaging, and the European Thyroid Association. Thyroid 2019,29, 461–470. [CrossRef]
4.
Bible, K.C.; Kebebew, E.; Brierley, J.; Brito, J.P.; Cabanillas, M.E.; Clark, T.J., Jr.; Di Cristofano, A.; Foote, R.; Giordano, T.;
Kasperbauer, J.; et al. 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid
Cancer. Thyroid 2021,31, 337–386. [CrossRef] [PubMed]
5.
Giannini, R.; Moretti, S.; Ugolini, C.; Macerola, E.; Menicali, E.; Nucci, N.; Morelli, S.; Colella, R.; Mandarano, M.; Sidoni, A.; et al.
Immune Profiling of Thyroid Carcinomas Suggests the Existence of Two Major Phenotypes: An ATC-Like and a PDTC-Like.
J. Clin. Endocrinol. Metab. 2019,104, 3557–3575. [CrossRef]
6.
Xu, X.; Rao, G.; Gaffud, M.J.; Ding, H.G.; Maki, G.; Klingemann, H.-G.; Groh, V.; Spies, T.; Caillat-Zucman, S.; Gattuso, P.; et al.
Clinicopathological significance of major histocompatibility complex class I-related chain A and B expression in thyroid cancer.
J. Clin. Endocrinol. Metab. 2006,91, 2704–2712. [CrossRef]
7.
Zhu, L.; Kalimuthu, S.; Oh, J.M.; Gangadaran, P.; Baek, S.H.; Jeong, S.Y.; Lee, S.-W.; Lee, J.; Ahn, B.-C. Enhancement of antitumor
potency of extracellular vesicles derived from natural killer cells by IL-15 priming. Biomaterials 2019,190–191, 38–50. [CrossRef]
8.
Gogali, F.; Paterakis, G.; Rassidakis, G.Z.; Kaltsas, G.; Liakou, C.I.; Gousis, P.; Neonakis, E.; Manoussakis, M.N.; Liapi, C.
Phenotypical Analysis of Lymphocytes with Suppressive and Regulatory Properties (Tregs) and NK Cells in the Papillary
Carcinoma of Thyroid. J. Clin. Endocrinol. Metab. 2012,97, 1474–1482. [CrossRef]
9.
Yin, M.; Di, G.; Bian, M. Dysfunction of natural killer cells mediated by PD-1 and Tim-3 pathway in anaplastic thyroid cancer. Int.
Immunopharmacol. 2018,64, 333–339. [CrossRef]

Vaccines 2024,12, 45 11 of 17
10.
Wennerberg, E.; Pfefferle, A.; Ekblad, L.; Yoshimoto, Y.; Kremer, V.; Kaminskyy, V.O.; Juhlin, C.C.; Höög, A.; Bodin, I.; Svjatoha, V.;
et al. Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract
NK Cells. Clin. Cancer Res. 2014,20, 5733–5744. [CrossRef]
11.
Park, A.; Lee, Y.; Kim, M.S.; Kang, Y.J.; Park, Y.-J.; Jung, H.; Kim, T.-D.; Lee, H.G.; Choi, I.; Yoon, S.R. Prostaglandin E2 Secreted by
Thyroid Cancer Cells Contributes to Immune Escape through the Suppression of Natural Killer (NK) Cell Cytotoxicity and NK
Cell Differentiation. Front. Immunol. 2018,9, 1859. [CrossRef] [PubMed]
12.
Hilly, O.; Koren, R.; Raz, R.; Rath-Wolfson, L.; Mizrachi, A.; Hamzany, Y.; Bachar, G.; Shpitzer, T. The Role of S100-Positive
Dendritic Cells in the Prognosis of Papillary Thyroid Carcinoma. Am. J. Clin. Pathol. 2013,139, 87–92. [CrossRef] [PubMed]
13.
Tsuge, K.; Takeda, H.; Kawada, S.; Maeda, K.; Yamakawa, M. Characterization of dendritic cells in differentiated thyroid cancer.
J. Pathol. 2005,205, 565–576. [CrossRef] [PubMed]
14.
Ugolini, C.; Basolo, F.; Proietti, A.; Vitti, P.; Elisei, R.; Miccoli, P.; Toniolo, A. Lymphocyte and Immature Dendritic Cell Infiltrates
in Differentiated, Poorly Differentiated, and Undifferentiated Thyroid Carcinoma. Thyroid 2007,17, 389–393. [CrossRef] [PubMed]
15.
Cunha, L.L.; Morari, E.C.; Guihen, A.C.T.; Razolli, D.; Gerhard, R.; Nonogaki, S.; Soares, F.A.; Vassallo, J.; Ward, L.S. Infiltration of
a mixture of immune cells may be related to good prognosis in patients with differentiated thyroid carcinoma. Clin. Endocrinol.
2012,77, 918–925. [CrossRef] [PubMed]
16.
Cunha, L.L.; Marcello, M.A.; Nonogaki, S.; Morari, E.C.; Soares, F.A.; Vassallo, J.; Ward, L.S. CD8+ tumour-infiltrating lymphocytes
and COX2 expression may predict relapse in differentiated thyroid cancer. Clin. Endocrinol. 2015,83, 246–253. [CrossRef] [PubMed]
17.
Yang, Z.; Yin, L.; Zeng, Y.; Li, Y.; Chen, H.; Yin, S.; Zhang, F.; Yang, W. Diagnostic and prognostic value of tumor-infiltrating B
cells in lymph node metastases of papillary thyroid carcinoma. Virchows Arch. 2021,479, 947–959. [CrossRef]
18.
Li, Y.-Y.; Li, S.-J.; Liu, M.-C.; Chen, Z.; Li, L.; Shen, F.; Liu, Q.-Z.; Xu, B.; Lian, Z.-X. B cells and tertiary lymphoid structures are
associated with survival in papillary thyroid cancer. J. Endocrinol. Investig. 2023,46, 2247–2256. [CrossRef]
19.
Qing, W.; Fang, W.-Y.; Ye, L.; Shen, L.-Y.; Zhang, X.-F.; Fei, X.-C.; Chen, X.; Wang, W.-Q.; Li, X.-Y.; Xiao, J.-C.; et al. Density of
Tumor-Associated Macrophages Correlates with Lymph Node Metastasis in Papillary Thyroid Carcinoma. Thyroid 2012,22,
905–910. [CrossRef]
20. Fang, W.; Ye, L.; Shen, L.; Cai, J.; Huang, F.; Wei, Q.; Fei, X.; Chen, X.; Guan, H.; Wang, W.; et al. Tumor-associated macrophages
promote the metastatic potential of thyroid papillary cancer by releasing CXCL8. Carcinogenesis 2014,35, 1780–1787. [CrossRef]
21.
Ryder, M.; Ghossein, R.A.; Ricarte-Filho, J.C.M.; Knauf, J.A.; Fagin, J.A. Increased density of tumor-associated macrophages is
associated with decreased survival in advanced thyroid cancer. Endocr.-Relat. Cancer 2008,15, 1069–1074. [CrossRef] [PubMed]
22.
Jung, K.Y.; Cho, S.W.; Kim, Y.A.; Kim, D.; Oh, B.-C.; Park, D.J.; Park, Y.J. Cancers with Higher Density of Tumor-Associated
Macrophages Were Associated with Poor Survival Rates. J. Pathol. Transl. Med. 2015,49, 318–324. [CrossRef] [PubMed]
23.
Angell, T.E.; Lechner, M.G.; Smith, A.M.; Martin, S.E.; Groshen, S.G.; Maceri, D.R.; Singer, P.A.; Epstein, A.L. Circulating Myeloid-
Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent. Thyroid 2016,26, 381–389. [CrossRef]
[PubMed]
24.
Suzuki, S.; Shibata, M.; Gonda, K.; Kanke, Y.; Ashizawa, M.; Ujiie, D.; Suzushino, S.; Nakano, K.; Fukushima, T.; Sakurai, K.; et al.
Immunosuppression involving increased myeloid-derived suppressor cell levels, systemic inflammation and hypoalbuminemia
are present in patients with anaplastic thyroid cancer. Mol. Clin. Oncol. 2013,1, 959–964. [CrossRef] [PubMed]
25.
Marone, G.; Varricchi, G.; Loffredo, S.; Granata, F. Mast cells and basophils in inflammatory and tumor angiogenesis and
lymphangiogenesis. Eur. J. Pharmacol. 2016,778, 146–151. [CrossRef]
26.
Detoraki, A.; Staiano, R.I.; Granata, F.; Giannattasio, G.; Prevete, N.; de Paulis, A.; Ribatti, D.; Genovese, A.; Triggiani, M.; Marone,
G. Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects. J. Allergy Clin. Immunol.
2009,123, 1142–1149.e5. [CrossRef]
27.
Galdiero, M.R.; Varricchi, G.; Marone, G. The immune network in thyroid cancer. Oncoimmunology 2016,5, e1168556. [CrossRef]
28.
Varricchi, G.; Galdiero, M.R.; Loffredo, S.; Marone, G.; Iannone, R.; Marone, G.; Granata, F. Are Mast Cells MASTers in Cancer?
Front. Immunol. 2017,8, 424. [CrossRef]
29.
Varricchi, G.; Galdiero, M.R.; Marone, G.; Granata, F.; Borriello, F.; Marone, G. Controversial role of mast cells in skin cancers. Exp.
Dermatol. 2017,26, 11–17. [CrossRef]
30.
Melillo, R.M.; Guarino, V.; Avilla, E.; Galdiero, M.R.; Liotti, F.; Prevete, N.; Rossi, F.W.; Basolo, F.; Ugolini, C.; de Paulis, A.; et al.
Mast cells have a protumorigenic role in human thyroid cancer. Oncogene 2010,29, 6203–6215. [CrossRef]
31.
Proietti, A.; Ugolini, C.; Melillo, R.M.; Crisman, G.; Elisei, R.; Santoro, M.; Minuto, M.; Vitti, P.; Miccoli, P.; Basolo, F. Higher
Intratumoral Expression of CD1a, Tryptase, and CD68 in a Follicular Variant of Papillary Thyroid Carcinoma Compared to
Adenomas: Correlation with Clinical and Pathological Parameters. Thyroid 2011,21, 1209–1215. [CrossRef] [PubMed]
32.
Liu, C.; Lee, J.; Liu, T.; Chang, Y.; Hsu, Y.; Cheng, S. Blood neutrophil-to-lymphocyte ratio correlates with tumor size in patients
with differentiated thyroid cancer. J. Surg. Oncol. 2013,107, 493–497. [CrossRef] [PubMed]
33.
Galdiero, M.R.; Varricchi, G.; Loffredo, S.; Bellevicine, C.; Lansione, T.; Ferrara, A.L.; Iannone, R.; di Somma, S.; Borriello, F.; Clery,
E.; et al. Potential involvement of neutrophils in human thyroid cancer. PLoS ONE 2018,13, e0199740. [CrossRef] [PubMed]
34.
French, J.D.; Weber, Z.J.; Fretwell, D.L.; Said, S.; Klopper, J.P.; Haugen, B.R. Tumor-Associated Lymphocytes and Increased FoxP3+
Regulatory T Cell Frequency Correlate with More Aggressive Papillary Thyroid Cancer. J. Clin. Endocrinol. Metab. 2010,95,
2325–2333. [CrossRef] [PubMed]

Vaccines 2024,12, 45 12 of 17
35.
French, J.D.; Kotnis, G.R.; Said, S.; Raeburn, C.D.; McIntyre, R.C., Jr.; Klopper, J.P.; Haugen, B.R. Programmed Death-1+ T Cells
and Regulatory T Cells Are Enriched in Tumor-Involved Lymph Nodes and Associated with Aggressive Features in Papillary
Thyroid Cancer. J. Clin. Endocrinol. Metab. 2012,97, E934–E943. [CrossRef]
36.
Liu, Y.; Yun, X.; Gao, M.; Yu, Y.; Li, X. Analysis of regulatory T cells frequency in peripheral blood and tumor tissues in papillary
thyroid carcinoma with and without Hashimoto’s thyroiditis. Clin. Transl. Oncol. 2015,17, 274–280. [CrossRef]
37.
Wang, X.; Li, J.; Lu, C.; Wang, G.; Wang, Z.; Liu, X.; Liu, B.; Wang, G.; Zhang, Q.; Yang, Q. IL-10-producing B cells in differentiated
thyroid cancer suppress the effector function of T cells but improve their survival upon activation. Exp. Cell Res. 2019,376,
192–197. [CrossRef]
38.
Ferrari, S.M.; Fallahi, P.; Galdiero, M.R.; Ruffilli, I.; Elia, G.; Ragusa, F.; Paparo, S.R.; Patrizio, A.; Mazzi, V.; Varricchi, G.; et al.
Immune and Inflammatory Cells in Thyroid Cancer Microenvironment. Int. J. Mol. Sci. 2019,20, 4413. [CrossRef]
39.
Angell, T.E.; Lechner, M.G.; Jang, J.K.; LoPresti, J.S.; Epstein, A.L. MHC Class I Loss Is a Frequent Mechanism of Immune Escape
in Papillary Thyroid Cancer That Is Reversed by Interferon and Selumetinib Treatment In Vitro.Clin. Cancer Res. 2014,20,
6034–6044. [CrossRef]
40.
Frank-Raue, K.; Rondot, S.; Raue, F. Molecular genetics and phenomics of RET mutations: Impact on prognosis of MTC. Mol. Cell.
Endocrinol. 2010,322, 2–7. [CrossRef]
41.
Fusco, A.; Grieco, M.; Santoro, M.; Berlingieri, M.T.; Pilotti, S.; Pierotti, M.A.; Della Porta, G.; Vecchio, G. A new oncogene in
human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987,328, 170–172. [CrossRef] [PubMed]
42.
Santoro, M.; Carlomagno, F.; Hay, I.D.; Herrmann, M.A.; Grieco, M.; Melillo, R.; Pierotti, M.A.; Bongarzone, I.; Della Porta, G.;
Berger, N. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J. Clin. Investig.
1992,89, 1517–1522. [CrossRef] [PubMed]
43.
Ruan, X.; Yi, J.; Hu, L.; Zhi, J.; Zeng, Y.; Hou, X.; Huang, J.; Gu, P.; Hao, W.; Gao, M.; et al. Reduced MHC class II expression in
medullary thyroid cancer identifies patients with poor prognosis. Endocr.-Relat. Cancer 2022,29, 87–98. [CrossRef] [PubMed]
44.
Chen, D.S.; Mellman, I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity 2013,39, 1–10. [CrossRef]
[PubMed]
45.
Varricchi, G.; Loffredo, S.; Marone, G.; Modestino, L.; Fallahi, P.; Ferrari, S.M.; de Paulis, A.; Antonelli, A.; Galdiero, M.R. The
Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition. Int. J. Mol. Sci. 2019,20, 3934. [CrossRef]
[PubMed]
46.
Zhang, P.; Guan, H.; Yuan, S.; Cheng, H.; Zheng, J.; Zhang, Z.; Liu, Y.; Yu, Y.; Meng, Z.; Zheng, X.; et al. Targeting myeloid derived
suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors. Nat.
Commun. 2022,13, 1588. [CrossRef]
47.
Angell, T.E.; Lechner, M.G.; Jang, J.K.; Correa, A.J.; LoPresti, J.S.; Epstein, A.L. BRAF
V600E
in Papillary Thyroid Carcinoma Is
Associated with Increased Programmed Death Ligand 1 Expression and Suppressive Immune Cell Infiltration. Thyroid 2014,24,
1385–1393. [CrossRef]
48.
Naoum, G.E.; Morkos, M.; Kim, B.; Arafat, W. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol.
Cancer 2018,17, 51. [CrossRef]
49.
Sekino, M.; Iwadate, M.; Yamaya, Y.; Matsumoto, Y.; Suzuki, S.; Mizunuma, H.; Nakano, K.; Nakamura, I.; Suzuki, S. Analysis of
Expression of Programmed Cell Death Ligand 1 (PD-L1) and BRAF
V600E
Mutation in Thyroid Cancer. Cancers 2023,15, 3449.
[CrossRef]
50.
Na, K.J.; Choi, H. Immune landscape of papillary thyroid cancer and immunotherapeutic implications. Endocr.-Relat. Cancer 2018,
25, 523–531. [CrossRef]
51.
Gunda, V.; Gigliotti, B.; Ndishabandi, D.; Ashry, T.; McCarthy, M.; Zhou, Z.; Amin, S.; Freeman, G.J.; Alessandrini, A.; Parangi, S.
Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent
model of orthotopic murine anaplastic thyroid cancer. Br. J. Cancer 2018,119, 1223–1232. [CrossRef] [PubMed]
52.
Park, S.-J.; Kang, Y.E.; Kim, J.-H.; Park, J.-L.; Baek, S.-W.; Chu, I.S.; Yi, S.; Lee, S.E.; Park, Y.J.; Chung, E.-J.; et al. Transcrip-
tomic Analysis of Papillary Thyroid Cancer: A Focus on Immune-Subtyping, Oncogenic Fusion, and Recurrence. Clin. Exp.
Otorhinolaryngol. 2022,15, 183–193. [CrossRef] [PubMed]
53.
Luo, Y.; Yang, Y.-C.; Shen, C.-K.; Ma, B.; Xu, W.-B.; Wang, Q.-F.; Zhang, Y.; Liao, T.; Wei, W.-J.; Wang, Y. Immune Checkpoint
Protein Expression Defines the Prognosis of Advanced Thyroid Carcinoma. Front. Endocrinol. 2022,13, 859013. [CrossRef]
[PubMed]
54.
Shi, X.; Li, C.-W.; Tan, L.-C.; Wen, S.-S.; Liao, T.; Zhang, Y.; Chen, T.-Z.; Ma, B.; Yu, P.-C.; Lu, Z.-W.; et al. Immune Co-inhibitory
Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study. J. Clin. Endocrinol.
Metab. 2021,106, 120–132. [CrossRef]
55.
Zhang, G.; Jiao, Q.; Shen, C.; Song, H.; Zhang, H.; Qiu, Z.; Luo, Q. Interleukin 6 regulates the expression of programmed cell
death ligand 1 in thyroid cancer. Cancer Sci. 2021,112, 997–1010. [CrossRef]
56.
Fozzatti, L.; Alamino, V.A.; Park, S.; Giusiano, L.; Volpini, X.; Zhao, L.; Stempin, C.C.; Donadio, A.C.; Cheng, S.-Y.; Pellizas, C.G.
Author Correction: Interplay of fibroblasts with anaplastic tumor cells promotes follicular thyroid cancer progression. Sci. Rep.
2019,9, 18772. [CrossRef]

Vaccines 2024,12, 45 13 of 17
57.
Stempin, C.C.; Geysels, R.C.; Park, S.; Palacios, L.M.; Volpini, X.; Motran, C.C.; Rodríguez, E.V.A.; Nicola, J.P.; Cheng, S.-Y.; Pellizas,
C.G.; et al. Secreted Factors by Anaplastic Thyroid Cancer Cells Induce Tumor-Promoting M2-like Macrophage Polarization
through a TIM3-Dependent Mechanism. Cancers 2021,13, 4821. [CrossRef]
58.
Cunha, L.L.; Morari, E.C.; Nonogaki, S.; Marcello, M.A.; Soares, F.A.; Vassallo, J.; Ward, L.S. Interleukin 10 expression is related to
aggressiveness and poor prognosis of patients with thyroid cancer. Cancer Immunol. Immunother. 2017,66, 141–148. [CrossRef]
59.
Todaro, M.; Zerilli, M.; Ricci-Vitiani, L.; Bini, M.; Alea, M.P.; Florena, A.M.; Miceli, L.; Condorelli, G.; Bonventre, S.; Di Gesù, G.;
et al. Autocrine Production of Interleukin-4 and Interleukin-10 Is Required for Survival and Growth of Thyroid Cancer Cells.
Cancer Res. 2006,66, 1491–1499. [CrossRef]
60.
Stassi, G.; Todaro, M.; Zerilli, M.; Ricci-Vitiani, L.; Di Liberto, D.; Patti, M.; Florena, A.; Di Gaudio, F.; Di Gesù, G.; De Maria, R.
Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer Res.
2003,63, 6784–6790.
61.
Fuziwara, C.S.; Saito, K.C.; Kimura, E.T. Interplay of TGF
β
signaling and microRNA in thyroid cell loss of differentiation and
cancer progression. Arch. Endocrinol. Metab. 2019,63, 536–544. [CrossRef] [PubMed]
62.
Li, Y.; He, J.; Wang, F.; Wang, X.; Yang, F.; Zhao, C.; Feng, C.; Li, T. Role of MMP-9 in epithelial-mesenchymal transition of thyroid
cancer. World J. Surg. Oncol. 2020,18, 181. [CrossRef] [PubMed]
63.
Rotondi, M.; Coperchini, F.; Chiovato, L. CXCL8 in thyroid disease: From basic notions to potential applications in clinical
practice. Cytokine Growth Factor Rev. 2013,24, 539–546. [CrossRef] [PubMed]
64.
Antonelli, A.; Ferrari, S.M.; Fallahi, P.; Frascerra, S.; Piaggi, S.; Gelmini, S.; Lupi, C.; Minuto, M.; Berti, P.; Benvenga, S.; et al.
Dysregulation of secretion of CXC
α
-chemokine CXCL10 in papillary thyroid cancer: Modulation by peroxisome proliferator-
activated receptor-γagonists. Endocr.-Relat. Cancer 2009,16, 1299–1311. [CrossRef] [PubMed]
65.
Rotondi, M.; Coperchini, F.; Pignatti, P.; Magri, F.; Chiovato, L. Metformin Reverts the Secretion of CXCL8 Induced by TNF-
α
in
Primary Cultures of Human Thyroid Cells: An Additional Indirect Anti-Tumor Effect of the Drug. J. Clin. Endocrinol. Metab. 2015,
100, E427–E432. [CrossRef] [PubMed]
66.
Liu, Z.; Sun, D.-X.; Teng, X.-Y.; Xu, W.-X.; Meng, X.-P.; Wang, B.-S. Expression of Stromal Cell-Derived Factor 1 and CXCR7 in
Papillary Thyroid Carcinoma. Endocr. Pathol. 2012,23, 247–253. [CrossRef] [PubMed]
67.
Liu, Z.; Yang, L.; Teng, X.; Zhang, H.; Guan, H. The involvement of CXCR7 in modulating the progression of papillary thyroid
carcinoma. J. Surg. Res. 2014,191, 379–388. [CrossRef]
68.
Lin, Y.; Ma, Q.; Li, L.; Wang, H. The CXCL12–CXCR4 axis promotes migration, invasiveness, and EMT in human papillary thyroid
carcinoma B-CPAP cells via NF-κB signaling. Biochem. Cell Biol. 2018,96, 619–626. [CrossRef]
69.
Werner, T.A.; Forster, C.M.; Dizdar, L.; Verde, P.E.; Raba, K.; Schott, M.; Knoefel, W.T.; Krieg, A. CXCR4/CXCR7/CXCL12-Axis in
Follicular Thyroid Carcinoma. J. Cancer 2018,9, 929–940. [CrossRef]
70.
Gong, Y.; Xu, F.; Deng, L.; Peng, L. Recognition of Key Genes in Human Anaplastic Thyroid Cancer via the Weighing Gene
Coexpression Network. BioMed Res. Int. 2022,2022, 2244228. [CrossRef]
71.
Song, Y.S.; Kim, M.J.; Sun, H.J.; Kim, H.H.; Shin, H.S.; Kim, Y.A.; Oh, B.-C.; Cho, S.W.; Park, Y.J. Aberrant Thyroid-Stimulating
Hormone Receptor Signaling Increases VEGF-A and CXCL8 Secretion of Thyroid Cancer Cells, Contributing to Angiogenesis and
Tumor Growth. Clin. Cancer Res. 2019,25, 414–425. [CrossRef] [PubMed]
72.
Visciano, C.; Prevete, N.; Liotti, F.; Marone, G. Tumor-Associated Mast Cells in Thyroid Cancer. Int. J. Endocrinol. 2015,
2015, 705169. [CrossRef] [PubMed]
73.
Antonelli, A.; Ferrari, S.M.; Fallahi, P.; Piaggi, S.; Di Domenicantonio, A.; Galleri, D.; Santarpia, L.; Basolo, F.; Ferrannini, E.;
Miccoli, P. Variable modulation by cytokines and thiazolidinediones of the prototype Th1 chemokine CXCL10 in anaplastic
thyroid cancer. Cytokine 2012,59, 218–222. [CrossRef] [PubMed]
74. Carmeliet, P. VEGF as a Key Mediator of Angiogenesis in Cancer. Oncology 2005,69 (Suppl. S3), 4–10. [CrossRef] [PubMed]
75.
Viglietto, G.; Maglione, D.; Rambaldi, M.; Cerutti, J.; Romano, A.; Trapasso, F.; Fedele, M.; Ippolito, P.; Chiappetta, G.; Botti, G.
Upregulation of vascular endothelial growth factor (VEGF) and downregulation of placenta growth factor (PlGF) associated with
malignancy in human thyroid tumors and cell lines. Oncogene 1995,11, 1569–1579. [PubMed]
76.
Gulubova, M.; Ivanova, K.; Ananiev, J.; Gerenova, J.; Zdraveski, A.; Stoyanov, H.; Vlaykova, T. VEGF expression, microvessel
density and dendritic cell decrease in thyroid cancer. Biotechnol. Biotechnol. Equip. 2014,28, 508–517. [CrossRef] [PubMed]
77.
Toth, E.; Benkone, V.Z.; Oroszlan, G.; Ulveczky, E. [Prenatal lead blood levels in a city heavily exposed to lead]. Orv. Hetil. 1989,
130, 2679–2681. [PubMed]
78.
Xing, M. BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Bases, and Clinical Implications. Endocr. Rev.
2007,28, 742–762. [CrossRef]
79.
Ma, M.; Lin, B.; Wang, M.; Liang, X.; Su, L.; Okose, O.; Lv, W.; Li, J. Immunotherapy in anaplastic thyroid cancer. Am. J. Transl.
Res. 2020,12, 974–988.
80.
Moretti, S.; Menicali, E.; Voce, P.; Morelli, S.; Cantarelli, S.; Sponziello, M.; Colella, R.; Fallarino, F.; Orabona, C.; Alunno,
A.; et al. Indoleamine 2,3-Dioxygenase 1 (IDO1) Is Up-Regulated in Thyroid Carcinoma and Drives the Development of an
Immunosuppressant Tumor Microenvironment. J. Clin. Endocrinol. Metab. 2014,99, E832–E840. [CrossRef]
81.
Yin, H.; Tang, Y.; Guo, Y.; Wen, S. Immune Microenvironment of Thyroid Cancer. J. Cancer 2020,11, 4884–4896. [CrossRef]
[PubMed]

Vaccines 2024,12, 45 14 of 17
82.
Alturki, N.A. Review of the Immune Checkpoint Inhibitors in the Context of Cancer Treatment. J. Clin. Med. 2023,12, 4301.
[CrossRef] [PubMed]
83.
Liu, C.; Yang, M.; Zhang, D.; Chen, M.; Zhu, D. Clinical cancer immunotherapy: Current progress and prospects. Front. Immunol.
2022,13, 961805. [CrossRef] [PubMed]
84.
Ahn, S.; Kim, T.H.; Kim, S.W.; Ki, C.S.; Jang, H.W.; Kim, J.S.; Kim, J.H.; Choe, J.-H.; Shin, J.H.; Hahn, S.Y.; et al. Comprehensive
screening for PD-L1 expression in thyroid cancer. Endocr.-Relat. Cancer 2017,24, 97–106. [CrossRef] [PubMed]
85.
Chowdhury, S.; Veyhl, J.; Jessa, F.; Polyakova, O.; Alenzi, A.; MacMillan, C.; Ralhan, R.; Walfish, P.G. Programmed death-ligand 1
overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget 2016,7, 32318–32328.
[CrossRef]
86.
Boruah, M.; Gaddam, P.; Agarwal, S.; Mir, R.; Gupta, R.; Sharma, M.; Deo, S.S.; Nilima, N. PD-L1 expression in rare and aggressive
thyroid cancers: A preliminary investigation for a role of immunotherapy. J. Cancer Res. Ther. 2023,19, 312. [CrossRef]
87.
Lin, J.; Qiu, Y.; Zheng, X.; Dai, Y.; Xu, T. The miR-199a-5p/PD-L1 axis regulates cell proliferation, migration and invasion in
follicular thyroid carcinoma. BMC Cancer 2022,22, 756. [CrossRef]
88.
Bongiovanni, M.; Rebecchini, C.; Saglietti, C.; Bulliard, J.-L.; Marino, L.; de Leval, L.; Sykiotis, G.P. Very low expression of PD-L1
in medullary thyroid carcinoma. Endocr.-Relat. Cancer 2017,24, L35–L38. [CrossRef]
89.
Shi, X.; Yu, P.-C.; Lei, B.-W.; Li, C.-W.; Zhang, Y.; Tan, L.-C.; Shi, R.-L.; Wang, J.; Ma, B.; Xu, W.-B.; et al. Association Between
Programmed Death-Ligand 1 Expression and Clinicopathological Characteristics, Structural Recurrence, and Biochemical
Recurrence/Persistent Disease in Medullary Thyroid Carcinoma. Thyroid 2019,29, 1269–1278. [CrossRef]
90.
Cameselle-García, S.; Abdulkader-Sande, S.; Sánchez-Ares, M.; Rodríguez-Carnero, G.; Garcia-Gómez, J.; Gude-Sampedro,
F.; Abdulkader-Nallib, I.; Cameselle-Teijeiro, J.M. PD-L1 expression and immune cells in anaplastic carcinoma and poorly
differentiated carcinoma of the human thyroid gland: A retrospective study. Oncol. Lett. 2021,22, 553. [CrossRef]
91.
Chintakuntlawar, A.V.; Rumilla, K.M.; Smith, C.Y.; Jenkins, S.M.; Foote, R.L.; Kasperbauer, J.L.; Morris, J.C.; Ryder, M.; Alsidawi,
S.; Hilger, C.; et al. Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy:
Results From a Retrospective Study. J. Clin. Endocrinol. Metab. 2017,102, 1943–1950. [CrossRef] [PubMed]
92.
Ito, T.; Okamoto, I.; Tokashiki, K.; Sato, H.; Okada, T.; Yamashita, G.; Nagao, T.; Hirai, H.; Saigusa, N.; Tsukahara, K. PD-L1
Expression and Survival Rates Using TPS and CPS for Nivolumab-treated Head-and-Neck Cancer. Anticancer. Res. 2022,42,
1547–1554. [CrossRef] [PubMed]
93.
Waldman, A.D.; Fritz, J.M.; Lenardo, M.J. A guide to cancer immunotherapy: From T cell basic science to clinical practice. Nat.
Rev. Immunol. 2020,20, 651–668. [CrossRef] [PubMed]
94.
Kumai, T.; Yamaki, H.; Kono, M.; Hayashi, R.; Wakisaka, R.; Komatsuda, H. Antitumor Peptide-Based Vaccine in the Limelight.
Vaccines 2022,10, 70. [CrossRef] [PubMed]
95.
Steurer, S.; Schneider, J.; Büscheck, F.; Luebke, A.M.; Kluth, M.; Hube-Magg, C.; Hinsch, A.; Höflmayer, D.; Weidemann, S.; Fraune,
C.; et al. Immunohistochemically detectable thyroglobulin expression in extrathyroidal cancer is 100% specific for thyroidal
tumor origin. Ann. Diagn. Pathol. 2021,54, 151793. [CrossRef] [PubMed]
96.
Li, H.; Zhou, X.; Wang, G.; Hua, D.; Li, S.; Xu, T.; Dong, M.; Cui, X.; Yang, X.; Wu, Y.; et al. CAR-T Cells Targeting TSHR
Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer. J. Clin. Endocrinol. Metab. 2022,107,
1110–1126. [CrossRef]
97.
Ehlers, M.; Kuebart, A.; Hautzel, H.; Enczmann, J.; Reis, A.-C.; Haase, M.; Allelein, S.; Dringenberg, T.; Schmid, C.; Schott, M.
Epitope-Specific Antitumor Immunity Suppresses Tumor Spread in Papillary Thyroid Cancer. J. Clin. Endocrinol. Metab. 2017,102,
2154–2161. [CrossRef]
98.
Liu, T.R.; Su, X.; Qiu, W.S.; Chen, W.C.; Men, Q.Q.; Zou, L.; Li, Z.Q.; Fu, X.Y.; Yang, A.K. Thyroid-stimulating hormone receptor
affects metastasis and prognosis in papillary thyroid carcinoma. Eur. Rev. Med. Pharmacol. Sci. 2016,20, 3582–3591.
99.
So, Y.K.; Son, Y.-I.; Baek, C.-H.; Jeong, H.-S.; Chung, M.K.; Ko, Y.-H. Expression of Sodium–Iodide Symporter and TSH Receptor
in Subclinical Metastatic Lymph Nodes of Papillary Thyroid Microcarcinoma. Ann. Surg. Oncol. 2012,19, 990–995. [CrossRef]
100.
Morishita, M.; Uchimaru, K.; Sato, K.; Ohtsuru, A.; Yamashita, S.; Kanematsu, T.; Yamashita, N. Thyroglobulin-pulsed human
monocyte-derived dendritic cells induce CD4+ T cell activation. Int. J. Mol. Med. 2004,13, 33–39. [CrossRef]
101.
Wuttke, M.; Papewalis, C.; Meyer, Y.; Kessler, C.; Jacobs, B.; Willenberg, H.S.; Schinner, S.; Kouatchoua, C.; Baehring, T.; Scherbaum,
W.A.; et al. Amino Acid-Modified Calcitonin Immunization Induces Tumor Epitope-Specific Immunity in a Transgenic Mouse
Model for Medullary Thyroid Carcinoma. Endocrinology 2008,149, 5627–5634. [CrossRef] [PubMed]
102.
Rowe, C.W.; Paul, J.W.; Gedye, C.; Tolosa, J.M.; Bendinelli, C.; McGrath, S.; Smith, R. Targeting the TSH receptor in thyroid cancer.
Endocr.-Relat. Cancer 2017,24, R191–R202. [CrossRef] [PubMed]
103.
Zhang, K.; Ge, S.-J.; Lin, X.-Y.; Lv, B.-B.; Cao, Z.-X.; Li, J.-M.; Xu, J.-W.; Wang, Q.-X. Intercellular adhesion molecule 1 is a sensitive
and diagnostically useful immunohistochemical marker of papillary thyroid cancer (PTC) and of PTC-like nuclear alterations in
Hashimoto’s thyroiditis. Oncol. Lett. 2016,11, 1722–1730. [CrossRef] [PubMed]
104.
Zhang, P.; Tao, C.; Shimura, T.; Huang, A.C.; Kong, N.; Dai, Y.; Yao, S.; Xi, Y.; Wang, X.; Fang, J.; et al. ICAM1 antibody drug
conjugates exert potent antitumor activity in papillary and anaplastic thyroid carcinoma. iScience 2023,26, 107272. [CrossRef]
[PubMed]
105.
Min, I.M.; Shevlin, E.; Vedvyas, Y.; Zaman, M.; Wyrwas, B.; Scognamiglio, T.; Moore, M.D.; Wang, W.; Park, S.; Park, S.; et al. CAR
T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors. Clin. Cancer Res. 2017,23, 7569–7583. [CrossRef]

Vaccines 2024,12, 45 15 of 17
106.
Gray, K.D.; McCloskey, J.E.; Vedvyas, Y.; Kalloo, O.R.; El Eshaky, S.; Yang, Y.; Shevlin, E.; Zaman, M.; Ullmann, T.M.; Liang, H.;
et al. PD1 Blockade Enhances ICAM1-Directed CAR T Therapeutic Efficacy in Advanced Thyroid Cancer. Clin. Cancer Res. 2020,
26, 6003–6016. [CrossRef]
107.
Vedvyas, Y.; McCloskey, J.E.; Yang, Y.; Min, I.M.; Fahey, T.J.; Zarnegar, R.; Hsu, Y.-M.S.; Hsu, J.-M.; Van Besien, K.; Gaudet, I.; et al.
Manufacturing and preclinical validation of CAR T cells targeting ICAM-1 for advanced thyroid cancer therapy. Sci. Rep. 2019,
9, 10634. [CrossRef]
108.
Pacini, F.; Basolo, F.; Elisei, R.; Fugazzola, L.; Cola, A.; Pinchera, A. Medullary Thyroid Cancer: An Immunohistochemical and
Humoral Study Using Six Separate Antigens. Am. J. Clin. Pathol. 1991,95, 300–308. [CrossRef]
109.
Schröder, S.; Böcker, W.; Baisch, H.; Bürk, C.G.; Arps, H.; Meiners, I.; Kastendieck, H.; Heitz, P.U.; Klöppel, G. Prognostic factors
in medullary thyroid carcinomas. Survival in relation to age, sex, stage, histology, immunocytochemistry, and DNA content.
Cancer 1988,61, 806–816. [CrossRef]
110.
Zhou, Q.S.J.; Yue, S.; Jing, J.; Yang, H.Y.; Zheng, Z.G.; Xu, H. Clinicopathological Characteristics of Medullary Thyroid Carcinoma
with the Expression of Thyroglobulin in East—China. Clin. Case Rep. Int. 2021,5, 1242.
111.
Bilusic, M.; Heery, C.R.; Arlen, P.M.; Rauckhorst, M.; Apelian, D.; Tsang, K.Y.; Tucker, J.A.; Jochems, C.; Schlom, J.; Gulley, J.L.;
et al. Phase I trial of a recombinant yeast-CEA vaccine (GI-6207) in adults with metastatic CEA-expressing carcinoma. Cancer
Immunol. Immunother. 2014,63, 225–234. [CrossRef] [PubMed]
112.
Madan, R.A.; Singh, N.K.; Gramza, A.W.; Fojo, A.T.; Heery, C.R.; Kim, J.W.; McMahon, S.; Rauckhorst, M.; King, T.H.; Apelian,
D.; et al. A phase II study of a yeast-based therapeutic cancer vaccine, GI-6207, targeting CEA in patients with minimally
symptomatic, metastatic medullary thyroid cancer. J. Clin. Oncol. 2013,31, TPS3127. [CrossRef]
113.
Schott, M.; Seissler, J.; Lettmann, M.; Fouxon, V.; Scherbaum, W.A.; Feldkamp, J. Immunotherapy for Medullary Thyroid
Carcinoma by Dendritic Cell Vaccination. J. Clin. Endocrinol. Metab. 2001,86, 4965–4969. [CrossRef] [PubMed]
114.
Martins, M.B.; Marcello, M.A.; Batista, F.d.A.; Cunha, L.L.; Morari, E.C.; Soares, F.A.; Vassallo, J.; Ward, L.S. CD8+ TIL Recruitment
May Revert the Association of MAGE A3 with Aggressive Features in Thyroid Tumors. J. Immunol. Res. 2014,2014, 92186.
[CrossRef] [PubMed]
115.
Milkovic, M.; Sarcevic, B.; Glavan, E. Expression of MAGE Tumor-Associated Antigen in Thyroid Carcinomas. Endocr. Pathol.
2006,17, 45–52. [CrossRef]
116.
Melo, D.H.; Mamede, R.C.M.; Neder, L.; Silva, W.A.; Barros-Filho, M.C.; Kowalski, L.P.; Pinto, C.A.L.; Zago, M.A.; Figueiredo,
D.L.A.; Jungbluth, A.A. Expression of cancer/testis antigens MAGE-A, MAGE-C1, GAGE and CTAG1B in benign and malignant
thyroid diseases. Oncol. Lett. 2017,14, 6485–6496.
117.
Guan, H.; Wu, Y.; Li, L.; Yang, Y.; Qiu, S.; Zhao, Z.; Chu, X.; He, J.; Chen, Z.; Zhang, Y.; et al. Tumor neoantigens: Novel strategies
for application of cancer immunotherapy. Oncol. Res. Featur. Preclin. Clin. Cancer Ther. 2023,31, 437–448. [CrossRef]
118.
Landa, I.; Ibrahimpasic, T.; Boucai, L.; Sinha, R.; Knauf, J.A.; Shah, R.H.; Dogan, S.; Ricarte-Filho, J.C.; Krishnamoorthy, G.P.; Xu,
B.; et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J. Clin. Investig. 2016,126,
1052–1066. [CrossRef]
119.
Yoo, S.-K.; Song, Y.S.; Lee, E.K.; Hwang, J.; Kim, H.H.; Jung, G.; Kim, Y.A.; Kim, S.-J.; Cho, S.W.; Won, J.-K.; et al. Integrative
analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer. Nat. Commun.
2019,10, 2764. [CrossRef]
120.
Nikiforov, Y.E. Genetic Alterations Involved in the Transition from Well-Differentiated to Poorly Differentiated and Anaplastic
Thyroid Carcinomas. Endocr. Pathol. 2004,15, 319–328. [CrossRef]
121.
Kebebew, E.; Weng, J.B.; Bauer, J.; Ranvier, G.; Clark, O.H.; Duh, Q.-Y.; Shibru, D.; Bastian, B.; Griffin, A. The Prevalence and
Prognostic Value of BRAF Mutation in Thyroid Cancer. Ann. Surg. 2007,246, 466–471. [CrossRef] [PubMed]
122.
Chung, K.; Yang, S.K.; Lee, G.K.; Kim, E.Y.; Kwon, S.; Lee, S.H.; Park, D.J.; Lee, H.S.; Cho, B.Y.; Lee, E.S.; et al. Detection
of BRAF
V600E
mutation on fine needle aspiration specimens of thyroid nodule refines cyto-pathology diagnosis, especially in
BRAFV600E mutation-prevalent area. Clin. Endocrinol. 2006,65, 660–666. [CrossRef] [PubMed]
123.
Kim, T.Y.; Kim, W.B.; Rhee, Y.S.; Song, J.Y.; Kim, J.M.; Gong, G.; Lee, S.; Kim, S.Y.; Kim, S.C.; Hong, S.J.; et al. The BRAF mutation
is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin. Endocrinol.
2006,65, 364–368. [CrossRef] [PubMed]
124.
Costa, A.M.; Herrero, A.; Fresno, M.F.; Heymann, J.; Alvarez, J.A.; Cameselle-Teijeiro, J.; García-Rostán, G. BRAF mutation
associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma. Clin. Endocrinol. 2008,68,
618–634. [CrossRef] [PubMed]
125.
Subbiah, V.; Kreitman, R.; Wainberg, Z.; Cho, J.; Schellens, J.; Soria, J.; Wen, P.; Zielinski, C.; Cabanillas, M.; Boran, A.; et al.
Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: Updated analysis from the phase II
ROAR basket study. Ann. Oncol. 2022,33, 406–415. [CrossRef]
126.
Al-Jundi, M.; Thakur, S.; Gubbi, S.; Klubo-Gwiezdzinska, J. Novel Targeted Therapies for Metastatic Thyroid Cancer—A
Comprehensive Review. Cancers 2020,12, 2104. [CrossRef]
127.
Tirrò, E.; Martorana, F.; Romano, C.; Vitale, S.R.; Motta, G.; Di Gregorio, S.; Massimino, M.; Pennisi, M.S.; Stella, S.; Puma, A.; et al.
Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice. Genes 2019,10, 709. [CrossRef]
128.
Brzezianska, E.; Pastuszak-Lewandoska, D. A minireview: The role of MAPK/ERK and PI3K/Akt pathways in thyroid follicular
cell-derived neoplasm. Front. Biosci. 2011,16, 422–439. [CrossRef]

Vaccines 2024,12, 45 16 of 17
129.
Ade, C.M.; Sporn, M.J.; Das, S.; Yu, Z.; Hanada, K.-I.; Qi, Y.A.; Maity, T.; Zhang, X.; Guha, U.; Andresson, T.; et al. Identification of
neoepitope reactive T-cell receptors guided by HLA-A*03:01 and HLA-A*11:01 immunopeptidomics. J. Immunother. Cancer 2023,
11, e007097. [CrossRef]
130.
Ehlers, M.; Schmidt, M.; Mattes-Gyorgy, K.; Antke, C.; Enczmann, J.; Schlensog, M.; Japp, A.; Haase, M.; Allelein, S.; Dringenberg,
T.; et al. BRAFV600E and BRAF-WT Specific Antitumor Immunity in Papillary Thyroid Cancer. Horm. Metab. Res. 2022,54,
852–858. [CrossRef]
131.
Rahdan, S.; Razavi, S.A.; Shojaeian, S.; Shokri, F.; Amiri, M.M.; Zarnani, A.-H. Immunization with placenta-specific 1 (plac1)
induces potent anti-tumor responses and prolongs survival in a mouse model of melanoma. Adv. Med. Sci. 2022,67, 338–345.
[CrossRef] [PubMed]
132.
Kumai, T.; Lee, S.; Cho, H.-I.; Sultan, H.; Kobayashi, H.; Harabuchi, Y.; Celis, E. Optimization of Peptide Vaccines to Induce
Robust Antitumor CD4 T-cell Responses. Cancer Immunol. Res. 2017,5, 72–83. [CrossRef] [PubMed]
133.
Yoshimura, K.; Minami, T.; Nozawa, M.; Kimura, T.; Egawa, S.; Fujimoto, H.; Yamada, A.; Itoh, K.; Uemura, H. A Phase 2 Random-
ized Controlled Trial of Personalized Peptide Vaccine Immunotherapy with Low-dose Dexamethasone Versus Dexamethasone
Alone in Chemotherapy-naive Castration-resistant Prostate Cancer. Eur. Urol. 2016,70, 35–41. [CrossRef] [PubMed]
134.
Kuwabara, K.; Nishishita, T.; Morishita, M.; Oyaizu, N.; Yamashita, S.; Kanematsu, T.; Obara, T.; Mimura, Y.; Inoue, Y.; Kaminishi,
M.; et al. Results of a Phase I Clinical Study Using Dendritic Cell Vaccinations for Thyroid Cancer. Thyroid 2007,17, 53–58.
[CrossRef]
135.
Del Rivero, J.; Donahue, R.N.; Marté, J.L.; Gramza, A.W.; Bilusic, M.; Rauckhorst, M.; Cordes, L.; Merino, M.J.; Dahut, W.L.;
Schlom, J.; et al. A Case Report of Sequential Use of a Yeast-CEA Therapeutic Cancer Vaccine and Anti-PD-L1 Inhibitor in
Metastatic Medullary Thyroid Cancer. Front. Endocrinol. 2020,11, 490. [CrossRef]
136.
Zhi, J.; Zhang, P.; Ruan, X.; Tian, M.; Guo, S.; Zhang, W.; Zheng, X.; Zhao, L.; Gao, M. Inhibition of BRAF Sensitizes Thyroid
Carcinoma to Immunotherapy by Enhancing tsMHCII-mediated Immune Recognition. J. Clin. Endocrinol. Metab. 2021,106,
91–107. [CrossRef]
137.
Brauner, E.; Gunda, V.; Borre, P.V.; Zurakowski, D.; Kim, Y.S.; Dennett, K.V.; Amin, S.; Freeman, G.J.; Parangi, S. Combining BRAF
inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent
murine model of anaplastic thyroid cancer. Oncotarget 2016,7, 17194–17211. [CrossRef]
138.
Gunda, V.; Gigliotti, B.; Ashry, T.; Ndishabandi, D.; McCarthy, M.; Zhou, Z.; Amin, S.; Lee, K.E.; Stork, T.; Wirth, L.; et al. Anti-
PD-1/PD-L1 therapy augments lenvatinib’s efficacy by favorably altering the immune microenvironment of murine anaplastic
thyroid cancer. Int. J. Cancer 2019,144, 2266–2278. [CrossRef]
139.
Bertol, B.C.; Bales, E.S.; Calhoun, J.D.; Mayberry, A.; Ledezma, M.L.; Sams, S.B.; Orlicky, D.J.; Donadi, E.A.; Haugen, B.R.; French,
J.D. Lenvatinib Plus Anti-PD-1 Combination Therapy for Advanced Cancers: Defining Mechanisms of Resistance in an Inducible
Transgenic Model of Thyroid Cancer. Thyroid 2022,32, 153–163. [CrossRef]
140.
Mehnert, J.M.; Varga, A.; Brose, M.S.; Aggarwal, R.R.; Lin, C.-C.; Prawira, A.; de Braud, F.; Tamura, K.; Doi, T.; Piha-Paul,
S.A.; et al. Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with advanced, PD-L1–positive
papillary or follicular thyroid cancer. BMC Cancer 2019,19, 196. [CrossRef]
141.
Capdevila, J.; Wirth, L.J.; Ernst, T.; Aix, S.P.; Lin, C.-C.; Ramlau, R.; Butler, M.O.; Delord, J.-P.; Gelderblom, H.; Ascierto, P.A.; et al.
PD-1 Blockade in Anaplastic Thyroid Carcinoma. J. Clin. Oncol. 2020,38, 2620–2627. [CrossRef] [PubMed]
142.
Hatashima, A.; Archambeau, B.; Armbruster, H.; Xu, M.; Shah, M.H.; Konda, B.; Limbach, A.L.; Sukrithan, V. An Evaluation of
Clinical Efficacy of Immune Checkpoint Inhibitors for Patients with Anaplastic Thyroid Carcinoma. Thyroid 2022,32, 926–936.
[CrossRef] [PubMed]
143.
Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.M.; Hwu, W.-J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi,
K.; et al. Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer. N. Engl. J. Med. 2012,366, 2455–2465.
[CrossRef] [PubMed]
144.
Ferris, R.L.; Blumenschein, G., Jr.; Fayette, J.; Guigay, J.; Colevas, A.D.; Licitra, L.; Harrington, K.; Kasper, S.; Vokes, E.E.; Even,
C.; et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N. Engl. J. Med. 2016,375, 1856–1867.
[CrossRef] [PubMed]
145.
Sakamuri, D.; Glitza, I.C.; Cuellar, S.L.B.; Subbiah, V.; Fu, S.; Tsimberidou, A.M.; Wheler, J.J.; Hong, D.S.; Naing, A.; Falchook,
G.S.; et al. Phase I Dose-Escalation Study of Anti–CTLA-4 Antibody Ipilimumab and Lenalidomide in Patients with Advanced
Cancers. Mol. Cancer Ther. 2018,17, 671–676. [CrossRef] [PubMed]
146.
Xing, Y.; Wang, Y.; Wu, X. Radiotherapy combined with immunotherapy successfully treated one case of anaplastic thyroid
cancer: A case report. Front. Oncol. 2023,13, 1125226. [CrossRef] [PubMed]
147.
Chintakuntlawar, A.V.; Yin, J.; Foote, R.L.; Kasperbauer, J.L.; Rivera, M.; Asmus, E.; Garces, N.I.; Janus, J.R.; Liu, M.C.; Ma, D.J.;
et al. A Phase 2 Study of Pembrolizumab Combined with Chemoradiotherapy as Initial Treatment for Anaplastic Thyroid Cancer.
Thyroid 2019,29, 1615–1622. [CrossRef]
148.
Iyer, P.C.; Dadu, R.; Gule-Monroe, M.; Busaidy, N.L.; Ferrarotto, R.; Habra, M.A.; Zafereo, M.; Williams, M.D.; Gunn, G.B.;
Grosu, H.; et al. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. J.
Immunother. Cancer 2018,6, 68. [CrossRef]

Vaccines 2024,12, 45 17 of 17
149.
Dierks, C.; Seufert, J.; Aumann, K.; Ruf, J.; Klein, C.; Kiefer, S.; Rassner, M.; Boerries, M.; Zielke, A.; la Rosee, P.; et al. Combination
of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.
Thyroid 2021,31, 1076–1085. [CrossRef]
150.
McCrary, H.C.; Aoki, J.; Huang, Y.; Chadwick, B.; Kerrigan, K.; Witt, B.; Hunt, J.P.; Abraham, D. Mutation based approaches to the
treatment of anaplastic thyroid cancer. Clin. Endocrinol. 2022,96, 734–742. [CrossRef]
151.
Shih, S.-R.; Chen, K.-H.; Lin, K.-Y.; Yang, P.-C.; Chen, K.-Y.; Wang, C.-W.; Chen, C.-N.; Lin, C.-F.; Lin, C.-C. Immunotherapy in
anaplastic thyroid cancer: Case series. J. Formos. Med. Assoc. 2022,121, 1167–1173. [CrossRef] [PubMed]
152.
Luongo, C.; Porcelli, T.; Sessa, F.; De Stefano, M.A.; Scavuzzo, F.; Damiano, V.; Klain, M.; Bellevicine, C.; Matano, E.; Troncone,
G.; et al. Combination of Lenvatinib and Pembrolizumab as Salvage Treatment for Paucicellular Variant of Anaplastic Thyroid
Cancer: A Case Report. Curr. Oncol. 2021,28, 5401–5407. [CrossRef] [PubMed]
153.
Higashiyama, T.; Sugino, K.; Hara, H.; Ito, K.-I.; Nakashima, N.; Onoda, N.; Tori, M.; Katoh, H.; Kiyota, N.; Ota, I.; et al. Phase II
study of the efficacy and safety of lenvatinib for anaplastic thyroid cancer (HOPE). Eur. J. Cancer 2022,173, 210–218. [CrossRef]
[PubMed]
154. Wirth, L.J.; Brose, M.S.; Sherman, E.J.; Licitra, L.; Schlumberger, M.; Sherman, S.I.; Bible, K.C.; Robinson, B.; Rodien, P.; Godbert,
Y.; et al. Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients With Anaplastic Thyroid
Cancer. J. Clin. Oncol. 2021,39, 2359–2366. [CrossRef] [PubMed]
155.
Takahashi, S.; Kiyota, N.; Yamazaki, T.; Chayahara, N.; Nakano, K.; Inagaki, L.; Toda, K.; Enokida, T.; Minami, H.; Imamura, Y.;
et al. A Phase II study of the safety and efficacy of lenvatinib in patients with advanced thyroid cancer. Futur. Oncol. 2019,15,
717–726. [CrossRef] [PubMed]
156.
Tahara, M.; Kiyota, N.; Yamazaki, T.; Chayahara, N.; Nakano, K.; Inagaki, L.; Toda, K.; Enokida, T.; Minami, H.; Imamura, Y.; et al.
Lenvatinib for Anaplastic Thyroid Cancer. Front. Oncol. 2017,7, 25. [CrossRef] [PubMed]
157.
Ma, D.-X.; Ding, X.-P.; Zhang, C.; Shi, P. Combined targeted therapy and immunotherapy in anaplastic thyroid carcinoma with
distant metastasis: A case report. World J. Clin. Cases 2022,10, 3849–3855. [CrossRef]
158.
Gui, L.; Liu, S.; Zhang, Y.; Shi, Y. A Remarkable and Durable Response to Sintilimab and Anlotinib in the First-Line Treatment of
an Anaplastic Thyroid Carcinoma without Targetable Genomic Alterations: A Case Report. OncoTargets Ther. 2021,14, 2741–2746.
[CrossRef]
159.
Li, J.; Zhang, X.; Mu, Z.; Sun, D.; Sun, Y.; Lin, Y. Response to apatinib and camrelizumab combined treatment in a radioiodine
refractory differentiated thyroid cancer patient resistant to prior anti-angiogenic therapy: A case report and literature review.
Front. Immunol. 2022,13, 943916. [CrossRef]
160.
Gui, L.; Zhu, Y.; Li, X.; He, X.; Ma, T.; Cai, Y.; Liu, S. Case report: Complete response of an anaplastic thyroid carcinoma patient
with NRAS Q61R/BRAF D594N mutations to the triplet of dabrafenib, trametinib and PD-1 antibody. Front. Immunol. 2023,
14, 1178682. [CrossRef]
161.
Song, Y.; Song, Y.; Bai, Y.; Bai, Y.; Wang, J.; Wang, J.; Xu, G.; Xu, G.; Wang, T.; Wang, T.; et al. Pathologic complete response after
neoadjuvant v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibition combined with immunotherapy therapy for
anaplastic thyroid carcinoma: A case report and literature review. Endocr. J. 2023,70, 223–228. [CrossRef] [PubMed]
162.
Komatsuda, H.; Wakisaka, R.; Kono, M.; Kumai, T.; Hayashi, R.; Yamaki, H.; Sato, R.; Nagato, T.; Ohkuri, T.; Kosaka, A.; et al.
Mitogen-activated protein kinase inhibition augments the T cell response against HOXB7-expressing tumor through human
leukocyte antigen upregulation. Cancer Sci. 2023,114, 399–409. [CrossRef] [PubMed]
163.
Kono, M.; Komatsuda, H.; Yamaki, H.; Kumai, T.; Hayashi, R.; Wakisaka, R.; Nagato, T.; Ohkuri, T.; Kosaka, A.; Ohara, K.; et al.
Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck
squamous cell carcinoma. OncoImmunology 2022,11, 2021619. [CrossRef] [PubMed]
164.
Tran, T.T.; Caulfield, J.I.; Zhang, L.; Schoenfeld, D.A.; Djureinovic, D.; Chiang, V.L.; Oria, V.O.; Weiss, S.A.; Olino, K.; Jilaveanu,
L.B.; et al. Lenvatinib or anti-VEGF in combination with anti–PD-1 differentially augments antitumor activity in melanoma.
J. Clin. Investig. 2023,8, e157347. [CrossRef]
165.
Hu, Y.; Guo, X.; Chen, H.; Chang, Q.; Lu, H.; Li, Y.; Chen, C. Constructing a thyroid cancer prognostic risk model based on CD8+
T cell associated genes. Central Eur. J. Immunol. 2022,47, 234–245. [CrossRef]
166.
Marth, C.; Tarnawski, R.; Tyulyandina, A.; Pignata, S.; Gilbert, L.; Kaen, D.; Rubio, M.J.; Frentzas, S.; Beiner, M.; Magallanes-Maciel,
M.; et al. Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment
of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Int. J. Gynecol. Cancer 2022,32, 93–100. [CrossRef]
167.
Xie, W.; Zeng, Y.; Hu, L.; Hao, J.; Chen, Y.; Yun, X.; Lin, Q.; Li, H. Based on different immune responses under the glucose
metabolizing type of papillary thyroid cancer and the response to anti-PD-1 therapy. Front. Immunol. 2022,13, 991656. [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.