Figure 4 - available via license: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Content may be subject to copyright.
Chemotherapy induced PD-L1 expression in esophageal orthotopic tumors. KYSE150 cells were injected into the mouse esophagus to form solid tumors, and the mice were randomized to treatment and control groups. After 1 week of treatment, the mice were sacrificed, and PD-L1 expression was evaluated by Western blotting and IHC staining. Carboplatin plus paclitaxel treatment (C+P) reduced (A) tumor size and (B) tumor weight. PD-L1 expression in the KYSE150 orthotopic tumors was higher in the C+P-treated group compared to the control group (ctrl), as demonstrated by (C) Western blotting and (D) IHC staining. Similarly, 5-FU plus cisplatin treatment also reduced (E) tumor size and (F) tumor weight. PD-L1 expression was also induced by 5-FU plus cisplatin treatment as detected in (G) Western blotting and (H) IHC staining. Each lane in C and G represents an individual orthotopic tumor from different mice. The scale bars in D and H represent 25 μm. * indicates a P value b .05.
Source publication
The current study reveals the clinicopathological association of PD-L1 in Hong Kong esophageal squamous cell carcinoma (ESCC) patients and the differential regulation of PD-L1 by standard first-line chemotherapy in ESCC. Immunohistochemical analysis of tissue microarray data from 84 Hong Kong ESCC patients shows that PD-L1 was expressed in 21% of t...
Contexts in source publication
Context 1
... 1 week of treatment, the mice were sacrificed and the orthotopic tumors were excised for the determination of PD-L1 by Western blotting and IHC staining. Expectedly, there was a statistically significant reduction of tumor size in the treatment group of both carboplatin plus paclitaxel (Figure 4, A and B) and 5-FU plus cisplatin (Figure 4, E and F) compared to the control, which indicates the effectiveness of the drug treatment. In concordance with our results using the in vitro model, the PD-L1 protein level was considerably higher in the treatment group compared to the control group for both treatments ( Figure 4, C and D and G and H). ...
Context 2
... 1 week of treatment, the mice were sacrificed and the orthotopic tumors were excised for the determination of PD-L1 by Western blotting and IHC staining. Expectedly, there was a statistically significant reduction of tumor size in the treatment group of both carboplatin plus paclitaxel (Figure 4, A and B) and 5-FU plus cisplatin (Figure 4, E and F) compared to the control, which indicates the effectiveness of the drug treatment. In concordance with our results using the in vitro model, the PD-L1 protein level was considerably higher in the treatment group compared to the control group for both treatments ( Figure 4, C and D and G and H). ...
Similar publications
Background:
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Chemotherapy, the treatment of choice in non-operable cases, achieves a dismal success rate, raising the need for new therapeutic options. In about 25% of NSCLC, the activating mutations of the KRAS oncogene define a subclass that cannot benefit from tyr...
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) have improved the survival of patients with non‐small cell lung cancer (NSCLC). Still, many patients do not respond to these inhibitors. PD‐L1 (CD274) expression, one of the factors that influences efficacy of immune checkpoint inhibi...
Citations
... For example, the drugs paclitaxel and docetaxel cause cells to accumulate at the G2-M phase, while flavopiridol treatment results in G1 and G2 phase accumulation [6,8]. Additionally, chemotherapy causes higher immunogenicity by increasing the potential for cancer cell debris to be recognized by the immune system but can also lead to an immunosuppressive TME by overexpression of PDL1 on cancer cells and immune cell death [9,10]. PDL1 or PD1 antibodies such as pembrolizumab block the interaction between PD1 and its ligands, PDL1 and PDL2. ...
We have developed a three dimensional hybrid multi-scale agent-based ODE PDE model including tumour immune interaction, cell cycle phases, oxygen and drug diffusion dynamics, the pharmacodynamics of chemotherapy, targeted therapies, immunotherapy, radiotherapy and the respective systemic exposure levels of pharmacological treatments (described by pharmacokinetic modelling). The aim of this model is to support a more detailed understanding of the spatial-temporal dynamic interactions between cancer cells, the relevant immune cells, and especially targeted therapies' molecular moieties, which are all expected to interact simultaneously in the tumour microenvironment. This interaction can then be further investigated in the context of combination therapies, thus making some inroads in the mechanistic understanding of positive and negative synergies when multiple therapies are administered within this complex system. The key scientific question this work addresses is the role of temporal sequencing in combination therapies, which require the simultaneous modelling of many relevant components of the system to be properly understood.
... PD-L1 expression is subject to alterations at both transcriptional and post-translational levels and exhibits variation across different tumor types [50,51]. Several oncogenic signaling-activated transcription factors (TFs) modulate PD-L1 expression at the transcriptional level [15,52,53], and specific anticancer chemotherapeutic agents impact PD-L1 transcription [37,54]. Post-translationally, studies suggest that CDK4 and GSK3B regulate PD-L1 protein stability and degradation [38,53,55,56]. ...
Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlighted Cyclin-dependent kinases 4 and 6 (CDK4/6) as pivotal cell cycle regulators gaining prominence in cancer studies. This study reveals that the CDK4/6 inhibitor, palbociclib can enhance PD-L1 gene transcription and surface expression in MCC cells by activating HIF2α. Inhibiting HIF2α with TC-S7009 effectively counteracts palbociclib-induced PD-L1 transcription and significantly intensifies cell death in MCC. Simultaneously, co-targeting CDK4/6 and HIF2α boosts ROS levels while suppressing SLC7A11, a key regulator of cellular redox balance, promoting ferroptosis- a form of immunogenic cell death linked to iron. Considering the rising importance of immunogenic cell death in immunotherapy, this strategy holds promise for improving future MCC treatments, markedly increasing immunogenic cell death various across various MCC cell lines, thus advancing cancer immunotherapy.
... This effect was associated with the involvement of the PI3K/Akt pathway [86]. Along the same line of thinking, a study on esophageal squamous-cell carcinoma reported the induction of PD-L1 after chemotherapeutic (carboplatin plus paclitaxel and 5-FU with cisplatin) treatments, mediated by the MAPK/ERK pathway [87]. 5-Fluorouracil (5-FU) also caused the induction of PD-L1 in gastrointestinal cancer cell lines [88]. ...
Autophagy is a catabolic process that is essential to the maintenance of homeostasis through the cellular recycling of damaged organelles or misfolded proteins, which sustains energy balance. Additionally, autophagy plays a dual role in modulating the development and progression of cancer and inducing a survival strategy in tumoral cells. Programmed cell death-ligand 1 (PD-L1) modulates the immune response and is responsible for maintaining self-tolerance. Because tumor cells exploit the PD-L1–PD-1 interaction to subvert the immune response, immunotherapy has been developed based on the use of PD-L1-blocking antibodies. Recent evidence has suggested a bidirectional regulation between autophagy and PD-L1 molecule expression in tumor cells. Moreover, the research into the intrinsic properties of PD-L1 has highlighted new functions that are advantageous to tumor cells. The relationship between autophagy and PD-L1 is complex and still not fully understood; its effects can be context-dependent and might differ between tumoral cells. This review refines our understanding of the non-immune intrinsic functions of PD-L1 and its potential influence on autophagy, how these could allow the survival of tumor cells, and what this means for the efficacy of anti-PD-L1 therapeutic strategies.
... Therefore, the inhibition of the MAPK/ERK signaling pathway may have a double effect on cancer cells, reducing PD-L1 expression and suppressing cancer cell survival. A previous study demonstrated the increases in ERK phosphorylation and PD-L1 expression in esophageal squamous cell carcinoma cells following standard chemotherapy treatments, which were attenuated by the inhibition of MEK [39]. Similarly, our research reported that treatment with 5-FU combined with the blockage of MEK/ERK signaling pathway reduced PD-L1 expression in the SCC4 cell line because the inhibition of MEK1/2 using either Refametinib or U0126 reduced the high levels of PD-L1 expression in the 5-FU-treated SCC4 cells. ...
(1) Background: Oral squamous cell carcinoma (OSCC) is a significant health burden worldwide. This study aimed to determine the potentials of Refametinib, an orally bioavailable selective MEK1/2 inhibitor, to increase the effectiveness of 5-Fluorouracil (5-FU), a common cytotoxic drug, in the SCC4 cell line. (2) Methods: SCC4 cells were treated with increasing concentrations of 5-FU, either alone or in combination with Refametinib. The chemosensitivity to treatment was assessed via cell viability assay, microscopic observation, colony formation assay, and detection of apoptotic markers using Western blotting. The whole-cell expression and surface expression of programmed death-ligand 1 (PD-L1), an immune checkpoint protein which contributes to chemoresistance and affects treatment response, were also determined using Western blotting and flow cytometry, respectively. (3) Results: The combined treatment suppressed cell proliferation and promoted apoptosis in a more potent way than 5-FU treatment alone did. Additionally, MEK/ERK inhibition mitigated 5-FU-induced PD-L1 upregulation. (4) Conclusions: This is the first report of an enhanced anticancer effect and reduced PD-L1 expression for the combination of 5-FU with Refametinib in OSCC, suggesting a new promising combination strategy.
... Zhang et al. [9] confirmed that in ESCC cell lines with EGFR high expression when the EGFR signal was activated, the expression of PD-L1 was significantly increased, and when the EGFR tyrosine kinase inhibitor was applied, the expression was significantly inhibited. Similarly, Ng et al. [10] demonstrated that the expression of PD-L1 was upregulated by EGFR and its regulation was through the EGFR/ERK pathway in ESCC. By activating the EGFR signal, the expression of PD-L1 increased significantly in an EGFR-dependent manner, and when the EGFR signal was blocked, the expression of PD-L1 dropped sharply. ...
... Previous research has confirmed that EGFR activation can induce the expression of PD-L1 by EGFR-PI3K-AKT, EGFR-Erk, and EGR-PLC-γ signal pathways in ESCC cell lines [9][10][11]. A recent study showed that overexpression of EGFR can mediate the immune escape of tumor cells by upregulating PD-L1 expression in head and neck cancers [22]. ...
Mesenchymal stem cells are a potential therapeutic candidate for cerebral infarction due to their anti-inflammatory proprieties. However, ensuring the engraftment of sufficient cells into the affected brain area remains a challenge. Herein, magnetic targeting techniques were used for the transplantation of a large number of cells noninvasively. Mice subjected to pMCAO surgery were administered MSCs labeled or not with iron oxide@polydopamine nanoparticles by tail vein injection. Iron oxide@polydopamine particles were characterized by transmission electron microscopy, and labeled MSCs were characterized by flow cytometry and their differentiation potential was assessed in vitro. Following the systemic injection of iron oxide@polydopamine-labeled MSCs into pMCAO-induced mices, magnetic navigation increased the MSCs localization to the brain lesion site and reduced the lesion volume. Treatment with iron oxide@polydopamine-labeled MSCs also significantly inhibited M1 microglia polarization and increased M2 microglia cell infiltration. Furthermore, western blotting and immunohistochemical analysis demonstrated that microtubule-associated protein 2 and NeuN levels were upregulated the brain tissue of mice treated with iron oxide@polydopamine-labeled MSCs. Thus, iron oxide@polydopamine-labeled MSCs attenuated brain injury and protected neurons by preventing pro-inflammatory microglia activation. Overall, the proposed iron oxide@polydopamine-labeled MSCs approach may overcome the major drawback of the conventional MSCs therapy for the treatment of cerebral infarction.
... Zhang et al. [9] confirmed that in ESCC cell lines with EGFR high expression when the EGFR signal was activated, the expression of PD-L1 was significantly increased, and when the EGFR tyrosine kinase inhibitor was applied, the expression was significantly inhibited. Similarly, Ng et al. [10] demonstrated that the expression of PD-L1 was upregulated by EGFR and its regulation was through the EGFR/ERK pathway in ESCC. By activating the EGFR signal, the expression of PD-L1 increased significantly in an EGFR-dependent manner, and when the EGFR signal was blocked, the expression of PD-L1 dropped sharply. ...
... Previous research has confirmed that EGFR activation can induce the expression of PD-L1 by EGFR-PI3K-AKT, EGFR-Erk, and EGR-PLC-γ signal pathways in ESCC cell lines [9][10][11]. A recent study showed that overexpression of EGFR can mediate the immune escape of tumor cells by upregulating PD-L1 expression in head and neck cancers [22]. ...
Our study aimed to observe the correlation between epidermal growth factor receptor (EGFR) and programmed cell death-ligand 1 (PD-L1) expression and evaluate prognostic potential of their co-expression in esophageal squamous cell carcinoma (ESCC) patients. EGFR and PD-L1 expression were evaluated by immunohistochemical analysis. We revealed that there was a positive correlation between EGFR and PD-L1 expression in ESCC (P = 0.004). According to the positive relationship between EGFR and PD-L1, all patients were divided into four groups: EGFR (+)/PD-L1 (+), EGFR (+)/PD-L1 (-), EGFR (-)/PD-L1 (+), and EGFR (-)/PD-L1 (-). In 57 ESCC patients without surgery, we found that EGFR and PD-L1 co-expression were statistically correlated with a lower objective response rate (ORR) (p = 0.029), overall survival (OS) (p = 0.018) and progression-free survival (PFS) (p = 0.045) than those with one or none positive protein. Furthermore, PD-L1 expression has a significant positive correlation with infiltration level of 19 immune cells, EGFR expression was significantly correlated with infiltration level of 12 immune cells. The infiltration level of CD8 T cell and B cell were negatively correlated with EGFR expression. On the contrary with EGFR, the infiltration level of CD8 T cell, and B cell were positively correlated with PD-L1 expression. In conclusion, EGFR and PD-L1 co-expression could predict poor ORR and survival in ESCC without surgery, indicating a subset of patients who may benefit from a combination of targeted therapy against EGFR and PD-L1, which may expand the population benefiting from immunotherapy and reduce the occurrence of hyper progressive diseases.
... However, the beneficial effects of chemotherapeutics combined with the antitumor effects of therapeutic antibodies (ADCC) may be counter-regulated by inducing immune checkpoints on tumor cells. We and others have shown that ADCC and also chemotherapies induce PD-L1 expression, leading to inhibited antibody-mediated tumor killing [20,21]. A chemoimmunotherapy therefore might be hindered by tumor cells harnessing immune checkpoint pathways to escape immune surveillance [18]. ...
Simple Summary
We investigated the effects of chemotherapeutics used for the frontline treatment of newly diagnosed high-risk neuroblastoma patients in combination with anti-GD2 antibody ch14.18/CHO (dinutuximab beta, DB) in the presence of immune cells in preclinical models of neuroblastoma. The combined treatment showed an up-to-17-fold-stronger and GD2-specific cytotoxic effect compared to the controls treated with chemotherapy alone in the presence or absence of immune cells. These findings further support a clinical evaluation of DB in combination with frontline induction therapy for high-risk neuroblastoma patients.
Abstract
Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The effects on stress ligand and checkpoint expression by neuroblastoma cells and on activation receptors of NK cells were determined by using flow cytometry. NK-cell activity was measured with a CD107a/IFN-γ assay. Long-term cytotoxicity was analyzed in three spheroid models derived from GD2-positive neuroblastoma cell lines (LAN-1, CHLA 20, and CHLA 136) expressing a fluorescent near-infrared protein. Chemotherapeutics combined with DB in the presence of immune cells improved cytotoxic efficacy up to 17-fold compared to in the controls, and the effect was GD2-specific. The activating stress and inhibitory checkpoint ligands on neuroblastoma cells were upregulated by the chemotherapeutics up to 9- and 5-fold, respectively, and activation receptors on NK cells were not affected. The CD107a/IFN-γ assay revealed no additional activation of NK cells by the chemotherapeutics. The synergistic effect of DB with chemotherapeutics seems primarily attributed to the combined toxicity of antibody-dependent cellular cytotoxicity and chemotherapy, which supports further clinical evaluation in frontline induction therapy.
... Another possibility is the combination of immune cell therapy with checkpoint inhibitors (e.g., Ipilimumab, Pembrolizumab) to decrease immune cell suppression. Several studies identified that chemotherapeutic treatments could increase PD-L1 expression on multiple tumor entities, including gynecologic malignancies [164,165]. A phase I clinical trial (NCT01711515) identified an increase in PD-1 expression in T cells following chemoradiation therapy in advanced cervical cancer [166]. ...
Cervical cancer is one of the most common malignancies in women, and the majority of cases are caused by infection with high-risk human papilloma virus (HPV) subtypes. Despite effective preventative measures, such as vaccinations against HPV, over 300,000 women die world-wide from cervical cancer each year. Once cervical cancer is diagnosed, treatment may consist of radial hysterectomy, or chemotherapy and radiotherapy, or a combination of therapies dependent upon the disease stage. Unfortunately, overall prognosis for patients with metastatic or recurrent disease remains poor. In these cases, immunotherapies may be useful based on promising preclinical work, some of which has been successfully translated to the clinic. For example, approaches using monoclonal antibodies directed against surface proteins important for control of immune checkpoints (i.e., immune checkpoint inhibitors) were shown to improve outcome in many cancer settings, including cervical cancer. Additionally, initial clinical studies showed that application of cytotoxic immune cells modified to express chimeric antigen receptors (CAR) or T cell receptors (TCR) for better recognition and elimination of tumor cells may be useful to control cervical cancer. This review explores these important topics, including strengths and limitations of standard and developing approaches, and how some novel treatment strategies may be optimally used to offer the best possible treatment for cervical cancer patients.
... However, the 5-year overall survival rate of esophageal cancer is still less than 20%, which poses a great challenge [32,33]. With the progression of molecular biology studies in esophageal cancer [34][35][36], several novel strategies, such as immunotherapy [37,38], have been utilized in esophageal cancer treatment. However, there is still a lack of a well-recognized molecular classification system in esophageal cancer, making it difficult to apply personalized therapy. ...
Esophageal squamous carcinoma (ESCC) is the major subtype of esophageal cancer in China, accounting for 90% of cases. Recent studies revealed that abnormalities in the Hippo/YAP axis are pervasive in ESCC and are recognized as the important driver of ESCC progression. Since the activity of Hippo signaling is controlled by phosphorylation cascade, it is a mystery why the major effector YAP is still over-activated when the cascade is inhibited. Several studies suggested that in addition to phosphorylation, other protein modifications such as ubiquitination also play important roles in manipulating Hippo/YAP signaling activity. Since YAP protein stability is controlled via an appropriate balance between E3 ubiquitin ligases and deubiquitinases, we performed deubiquitinase siRNA screening and identified USP36 as a deubiquitinase significantly related to Hippo/YAP signaling activity and ESCC progression. USP36 expression was elevated in ESCC samples and correlated with poor differentiation. USP36 expression was correlated with YAP protein levels in ESCC samples. Molecular studies demonstrated that USP36 associated with the YAP protein and enhanced YAP protein stability by blocking the K48-linked polyubiquitination of YAP. In conclusion, our study revealed a novel deubiquitinase in regulating Hippo signaling in ESCC, which could be an encouraging drug target for Hippo-driven ESCC.
... Radiation also induced the phosphorylation of EGFR and STAT3, but AG1478 blocked this effect in KYSE-30 and TE-1 cells. Ng et al. [68] reported that EGFR and ERK (its downstream modulator) regulated PD-L1 expression in ESCC cells, and that erlotinib (an EGFR inhibitor) notably reduced PD-L1 expression in KYSE-150 cells in vitro and in vivo. They also found that 5-FU+cisplatin or carboplatin+paclitaxel upregulated PD-L1 and activated ERK signaling in KYSE-150 and SLMT cells, but treatment with erlotinib or AZD6244 (selumetinib, a MEK inhibitor) attenuated the upregulation of PD-L1 induced by chemotherapy in these cells. ...
... A meta-analysis by Yu et al. [11] analyzed 19 clinical studies and found that 31.8% of the samples were PD-L1 positive. Other studies reported that PD-L1 expression was greater in ESCC tumor tissues than adjacent normal tissues [68] and that positive PD-L1 expression was significantly associated with more advanced T stage (III and IV), lymph node metastasis, and poor differentiation [11]. The meta-analysis by Yu et al. [11] also reported that PD-L1 overexpression in ESCC had an et al. [71] showed that contraction of C-X-C motif chemokine ligand 6 (CXCL6), which is released from M2 tumor-associated macrophages, upregulated PD-L1 expression by activating STAT3 signaling via phosphorylation of STAT3 to p-STAT3 at 705th serine, promoted the EMT, and enhanced the growth and metastases of ESCC cells in vitro and in vivo. ...
Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer in China and developing countries. The purpose of this review is to summarize the roles of inactivation of the tumor suppressor gene, phosphatase and tensin homolog (PTEN), and activation of the programmed cell death protein 1 (PD-1) upon binding to its ligand (PD-L1) in the promotion of ESCC. Studies of ESCC performed in vitro and in vivo indicated that PTEN and PD-L1 function in the regulation of cell proliferation, invasion, and migration; the epithelial-mesenchymal transition; resistance to chemotherapy and radiotherapy; and the PI3K/AKT signaling pathway. Certain genetic variants of PTEN are related to susceptibility to ESCC, and PTEN and PD-L1 also function in ESCC progression and affect the prognosis of patients with ESCC. There is also evidence that the expression of PD-L1 and PTEN are associated with the progression of certain other cancers. Future studies should further examine the relationship of PD-L1 and PTEN and their possible interactions in ESCC.
