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Representative immunohistochemical staining of MHC class I molecules in metastatic lymph nodes (B) and the liver (D) of ESCC patients. Serial sections for haematoxylin–eosin (HE) staining are shown in (A) and (C).
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As antigenic peptides in the context of human leukocyte antigen (HLA) class I molecules are recognised by cytotoxic T lymphocytes (CTL), the downregulation of HLA class I molecules is one of the reasons why tumour cells can evade CTL-mediated anti-tumour immunity. In this study, we investigated HLA class I expression in oesophageal squamous cell ca...
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Background
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Citations
... Notably, it is important for pathologists to evaluate HLA class I molecules on the cell surface, but not in the cytoplasm (120). In surgically resected specimens, a decrease of HLA class I molecules is correlated to a poor prognosis in various types of malignancy, indicating that immune surveillance also inhibits the further growth of an established tumor (118,(121)(122)(123)(124). Nearly all current strategies for CTL-mediated immunotherapy cannot theoretically surmount the loss of HLA class I molecules, which is a serious problem for the future of cancer immunotherapy ( Figure 5B). ...
Extensive research over 100 years has demonstrated that tumors can be eliminated by the autologous immune system. Without doubt, immunotherapy is now a standard treatment along with surgery, chemotherapy, and radiotherapy; however, the field of cancer immunotherapy is continuing to develop. The current challenges for the use of immunotherapy are to enhance its clinical efficacy, reduce side effects, and develop predictive biomarkers. Given that histopathological analysis provides molecular and morphological information on humans in vivo, its importance will continue to grow. This review article outlines the basic knowledge that is essential for the research and daily practice of immune checkpoint inhibitor-based cancer immunotherapy from the perspective of histopathology.
... A second line of evidence for the clinical significance of MHC I-loss, comes from studies that have correlated MHC I expression with prognosis. In many cancers, including melanoma, glioblastoma, colorectal, bladder, uterine, cervical, head/neck, breast and other cancers, loss of MHC I is associated with worse clinical outcomes (14,110,111,(122)(123)(124)(125)(126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140). Since loss of the MHC I antigen presentation pathway does not alter intrinsic cell growth or viability, this correlation is also consistent with a role for antigen presentation in immune control of cancers (128). ...
Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.
... In addition to CTLA-4 and PD-1 axes-mediated mechanisms, tumor immune evasion involves other related processes (19), selectively and briefly described as follows, some of which may represent therapeutic targets: (i) Neoangiogenesis induced by tumor associated macrophages exacerbates hypoxia and lowers the microenvironment pH, leading to PD-L1 upregulation and impairment of CTLs proliferation and efficiency (20)(21)(22); (ii) Chemokines and molecules, such as vascular endothelial growth factor (VEGF), interleukin 10 (IL-10), prostaglandin E2 and TGF-b, produced by Tregs and myeloid-derived suppressor cells (MDSCs), as well endothelial cells, reduce the attraction of CTLs (23). On the other hand, release of CXCL8, CCL2, CXCL5, and CXCL12, CCL22, and CCL28 attracts Tregs (24); (iii) Arrest of clonal expansion of CTLs, mediated by tumor cell, dendritic cell, and MDSCs secretion of indolamine-2,3oxygenase (IDO), which induces degradation of tryptophan, an indispensable molecule for CTLs growth and production of Granzyme B (25); (iv) Impaired expression of human lymphocyte antigen-I (HLA-I) and other molecules involved in the antigen presentation machinery, leading to reduced tumor antigen recognition, impaired immune response, and worse prognosis (26,27). Genetic alterations identified by The Cancer Genomic Atlas Network (TCGA), such as mutations in KMTD2 and HLA-A, contribute to this immunosuppressive behavior (28). ...
Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of de novo resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of de novo and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.
... They can dampen the activation of NK cells after interacting with the human leukocyte antigen (HLA) ligands expressed on the surface of normal cells [21,22]. Tumor cells downregulate HLA to escape from the T cells immune surveillance [23][24][25]. Data from the Human Protein Atlas Database demonstrate that HLA-C is low or non-expressed on most tumor cell lines, but highly or moderately expressed in normal tissues. PD-1 is an inhibitory protein expressed in activated T cells to limit the excessive activation of T cells [26][27][28]. ...
Simple Summary
CD19-targeted chimeric antigen receptor (CAR) T (CD19-CAR-T) cell therapy usually causes B cell aplasia because of “on-target off-tumor” toxicity. The aim of the study was to assess the concept that the introduction of an inhibitory CAR (iCAR) into CAR-T cells could alleviate the side effect of CD19-CAR-T cell therapy. The results showed that CD19-CAR-T cells with a novel KIR (killer inhibitory receptor) /PD-1 (programmed death receptor-1)-based inhibitory CAR (iKP-19-CAR-T) exhibited more naïve, less exhausted phenotypes and preserved a higher proportion of central memory T cells (TCM). Furthermore, iKP-19-CAR-T cells exerted the similar level of cytotoxicity on CD19⁺HLA-C1⁻ Burkitt’s lymphoma cells compared to CD19-CAR-T cells while sparing CD19⁺HLA-C1⁺ healthy human B cells both in vitro and in the xenograft model. Our data demonstrates that the KIR/PD-1-based inhibitory CAR can be a promising strategy to avoid B cell aplasia caused by CD19-CAR-T cell therapy.
Abstract
B cell aplasia caused by “on-target off-tumor” toxicity is one of the clinical side effects during CD19-targeted chimeric antigen receptor (CAR) T (CD19-CAR-T) cells treatment for B cell malignancies. Persistent B cell aplasia was observed in all patients with sustained remission, which increased the patients’ risk of infection. Some patients even died due to infection. To overcome this challenge, the concept of incorporating an inhibitory CAR (iCAR) into CAR-T cells was introduced to constrain the T cells response once an “on-target off-tumor” event occurred. In this study, we engineered a novel KIR/PD-1-based inhibitory CAR (iKP CAR) by fusing the extracellular domain of killer cell immunoglobulin-like receptors (KIR) 2DL2 (KIR2DL2) and the intracellular domain of PD-1. We also confirmed that iKP CAR could inhibit the CD19 CAR activation signal via the PD-1 domain and CD19-CAR-T cells bearing an iKP CAR (iKP-19-CAR-T) exerted robust cytotoxicity in vitro and antitumor activity in the xenograft model of CD19⁺HLA-C1⁻ Burkitt’s lymphoma parallel to CD19-CAR-T cells, whilst sparing CD19⁺HLA-C1⁺ healthy human B cells both in vitro and in the xenograft model. Meanwhile, iKP-19-CAR-T cells exhibited more naïve, less exhausted phenotypes and preserved a higher proportion of central memory T cells (TCM). Our data demonstrates that the KIR/PD-1-based inhibitory CAR can be a promising strategy for preventing B cell aplasia induced by CD19-CAR-T cell therapy.
... The immune-intermediate subtype predominantly harbored low expression of HLA class I or both class I and II genes. Low HLA class I gene expression was associated with low immune infiltration, an absence of T-cell activation, and earlier relapse, in all corroborating that low HLA class I gene expression results in poor prognosis in solid cancers [51,52]. This observation is also in agreement with the bad prognosis linked to low immune infiltration we observed in PCNSL. ...
Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Bulk mRNA-sequencing (n=20) and microarray (n=34) data were exploited to identify three immune subtypes of PCNSL: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, e.g., IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/β-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints, i.e., CTLA-4/CD86 and TIM-3/LAGLS9. Immunohistopathology and digital imaging showed that TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.
... Nineteen studies had not met inclusion criteria, three studies were on other class of HLA (include G or E) [24][25][26] and in the three studies the information about survival analysis were not extractable 10,19,27 and all mentioned were excluded. Finally 10 studies were include in the meta-analysis 13,[28][29][30][31][32][33][34][35][36] . The flow chart of the literature search is as Fig. 1. ...
... There were 8 studies performing follow up which had reported HLA expression and OS for patients [28][29][30][31][32][33][34][35] . Using fixed model, the pooled HR was 0.70; 95% CI (0.62, 0.81), P = 0.03 with I 2 = 0.76%, P = 0.00. ...
... Radiotherapy, chemotherapy or resection were the patient treatments. We performed meta-analysis for predominant treatment which was included surgery (member or tumor removing) 13,[29][30][31][32]34,35 and non-surgery (radiotherapy or chemotherapy) 33,36 as shown in Table 2. www.nature.com/scientificreports www.nature.com/scientificreports/ ...
The prognostic role of Human leukocyte antigen class I (HLA- I) in gastrointestinal cancers has been remained controversial. We performed a meta-analysis to determine the role of classical HLA-I in predicting survival of patients. In addition, the relationship between HLA- I and some clinicopathological factors was evaluated. Published studies investigated HLA-I expression effect on gastrointestinal cancers were evaluated to determine association between HLA- I and overall survival (OS) and recurrence-free survival (RFS) in patients. The used effect sizes were hazard ratio (HR) and Odds ratio (OR) with 95% confidence interval (CI). A total of ten studies included 1307 patients were analyzed. The pooled results revealed that HLA- I overexpression was positively related to OS (HR: 0.72; 95% CI: 0.53–0.96) and demonstrated little association for RFS (HR: 0.70; 95% CI: 0.46–1.08). HLA-I overexpression is negative associated with poorer differentiation of tumor (OR: 0.53; 95% CI (0.43–0.81) and also higher stages of cancer (OR: 0.29; 95% CI (0.13–0.64). HLA- I overexpression was related to a better prognosis on OS and probably had little impact on RFS.
... These alternatives have been less explored in solid cancers as opposed to the adoptive transfers of chimeric antigen receptor (CAR) T-cells and tumor immune infiltrating T-cells (TILs). TILs have an obligation of MHC/HLA restriction, which limits their functional ability when the tumor cells downregulate MHC expression (85,107). CARs, although being not MHC restricted, require a homogenous expression of the targeted tumor antigen on the entire tumor cell population, a prerequisite not met in most cases, unlike hematologic neoplasms (108). ...
Treatment of solid tumors by ablation techniques has gained momentum in the recent years due to their technical simplicity and reduced morbidity as juxtaposed to surgery. Cryoablation is one of such techniques, known for its uniqueness to destroy the tumors by freezing to lethal temperatures. Freezing the tumor locally and allowing it to remain in situ unleashes an array of tumor antigens to be exposed to the immune system, paving the way for the generation of anti-tumor immune responses. However, the immune responses triggered in most cases are insufficient to eradicate the tumors with systemic spread. Therefore, combination of cryoablation and immunotherapy is a new treatment strategy currently being evaluated for its efficacy, notably in patients with metastatic disease. This article examines the mechanistic fabric of cryoablation for the generation of an effective immune response against the tumors, and various possibilities of its combination with different immunotherapies that are capable of inducing exceptional therapeutic responses. The combinatorial treatment avenues discussed in this article if explored in sufficient profundity, could reach the pinnacle of future cancer medicine.
... Furthermore, among the HLA class I APM chaperones, calreticulin and tapasin expression has been found to be associated with a favorable 5 year survival rate in colorectal cancer [54,55], while tapasin downregulation has been found to be a poor prognostic marker in laryngeal squamous cell carcinoma [56]. Lastly, defective HLA class I expression has been reported to be associated with poor overall survival in head and neck cancer [56][57][58][59], esophageal cancer [60][61][62][63][64], and melanoma [19,53]. ...
Malignant transformation of cells is frequently associated with defective HLA class I antigen processing machinery (APM) component expression. This abnormality may have functional relevance, since it may have a negative impact on tumor cell recognition by cognate T cells. Furthermore, HLA class I APM abnormalities appear to have clinical significance, since they are associated with poor prognosis in several malignant diseases and may play a role in the resistance to immune checkpoint inhibitor-based immunotherapy. In this paper, we have reviewed the literature describing abnormalities in HLA class I APM component expression in many types of cancer. These abnormalities have been reported in all types of cancer analyzed with a frequency ranging between a minimum of 35.8% in renal cancer and a maximum of 87.9% in thyroid cancer for HLA class I heavy chains. In addition, we have described the molecular mechanisms underlying defects in HLA class I APM component expression and function by malignant cells. Lastly, we have discussed the clinical significance of HLA class I APM component abnormalities in malignant tumors.
... Indeed, in the meanwhile, several immune escape mechanisms have been described. For example, tumors often escape immune surveillance by losing MHC class I or costimulatory molecules expression or by rendering APC and CTL anergic or suppressive [7][8][9]. In addition, tumor cells can release immunosuppressive cytokines such as interleukin-10 (IL-10) or transforming growth factor-b1 (TGF-b1), which can not only inhibit anti-tumor immune responses but also increase proliferation of tumor cells in an auto-and paracrine manner [10,11]. ...
Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4\(^+\) and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4\(^+\) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8\(^+\) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics.
... Staining was classified as follows: Grade 0, <10% stained cells; Grade 2, 10–50% stained cells; Grade 3, 50–90% stained cells; Grade 4, >90% stained cells. The relationship between HLA class I expression and clinical prognosis was assessed by dividing the post-HCRT specimens into two groups, as previously described [6], [13], [19]: Grades 0–1 and Grades 2–3. The relationship between HLA class I expression and clinical prognosis was not examined in pre-HCRT specimens because only one patient showed Grade 2–3 expression prior to HCRT. ...
Objective
Enhancing immunologic responses, including human leukocyte antigen (HLA) class I expression on tumor cells and recognition and elimination of tumor cells by tumor-specific cytotoxic T lymphocyte (CTL), is considered a novel concept of radiotherapy. The present study examined patients who underwent preoperative hyperthermo-chemoradiotherapy (HCRT) for locally advanced rectal cancer to assess the correlation between HLA class I expression and clinical outcome.
Materials and Methods
Seventy-eight patients with locally advanced rectal adenocarcinoma who received preoperative HCRT were enrolled. The median age of the patients was 64 years (range, 33–85 years) and 4, 18, and 56 patients had clinical stage I, II and III disease, respectively. Formalin-fixed and paraffin-embedded tissues excised before and after HCRT were subjected to immunohistochemical analysis with an anti-HLA class I-A, B, C antibody. HLA class I expression was graded according to tumor cell positivity.
Results
In pre-HCRT, the number of specimens categorized as Grade 0 and 1 were 19 (24%) and 58 (74%), respectively. Only 1 patient (1%) showed Grade 2 expression. However, 6 (8%), 27 (35%), 7 (9%), and 12 (15%) post-HCRT specimens were graded as Grade 0, 1, 2, and 3, respectively. There was a significant increase in HLA class I expression in post-HCRT specimens (p<0.01). However, neither pre- nor post-HCRT HLA class I expression affected overall survival and distant metastasis-free survival in clinical stage III patients. Univariate analysis revealed that Post-HCRT HLA class I expression showed a significant negative relationship with LC (p<0.05). Nevertheless, multivariate analysis showed that there was no correlation between HLA class I expression and clinical outcome.
Conclusion
HCRT increased HLA class I expression in rectal cancer patients. However, multivariate analysis failed to show any correlation between the level of HLA class I expression and prognosis.
