PD-L1 expression is associated with epithelial-mesenchymal transition in head and neck squamous cell carcinoma

Ock, Chan Young; Kim, Sehui; Keam, Bhumsuk; Kim, Miso; Kim, Tae Min; Kim, Jin Ho; Jeon, Yoon Kyung; Lee, Ju Seog; Kwon, Seong Keun; Hah, J. Hun; Kwon, Taekyoung; Wu, Hong Gyun; Sung, Myung Whun; Heo, Dae Seog

doi:10.18632/oncotarget.7431

Cited by 135 publications

(140 citation statements)

References 54 publications

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“…The differences observed in the positivity rate of PD-L1 in ESCC may be attributed to the antibodies used in the IHC staining and the scoring criteria for the staining. The positivity rate of PD-L1 is also dependent on whether the patients received any treatment before sample collection since chemotherapy and radiotherapy induce PD-L1 expression, as demonstrated by our current study and other reports [8], [26], [27]. Previous studies demonstrate that high PD-L1 expression is associated with advanced disease and lymph node metastasis in various cancers [28], [29], [30].…”

Section: Discussionsupporting

confidence: 80%

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

Tao

et al. 2018

Translational Oncology

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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 the tumors. Positive PD-L1 staining was significantly associated with later disease stage (stages III and IV) (P value = .0379) and lymph node metastasis (P value = .0466) in the Hong Kong cohort. Furthermore, PD-L1 expression was significantly induced in ESCC cell lines after standard chemotherapy treatments, along with EGFR and ERK activation in both in vitro studies and the in vivo esophageal orthotopic model. The endogenous expression of PD-L1 was reduced by treatment with an EGFR inhibitor (erlotinib) or by the knockdown of EGFR. Moreover, the upregulation of PD-L1 by chemotherapy was also attenuated by the treatment with erlotinib and a MAPK/MEK inhibitor (AZD6244), suggesting that PD-L1 is regulated by the EGFR/ERK pathway in ESCC. The regulation of PD-L1 by the EGFR pathway was further supported by the correlation of PD-L1 and EGFR expression observed in the commercially available tissue microarray set (P value = .028). Taken together, the current study was the first to demonstrate the upregulation of PD-L1 by chemotherapy in ESCC and its regulation through the EGFR/ERK pathway. The results suggest the potential usefulness of combined conventional chemotherapy together with anti–PD-L1 immunotherapy to achieve better treatment outcome.

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Section: Discussionsupporting

confidence: 80%

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

Tao

et al. 2018

Translational Oncology

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“…Many recent studies have highlighted the critical role of PD-L1 in regulating the biological functions of cancer cells themselves, including cell proliferation, migration, metastasis, chemo/radio-resistance, and the promotion of epithelial to mesenchymal transition [9,10,18,21,23,[30][31][32]. It has been suggested that signal pathways such as JAK/ STAT1/IRF-1, MEK/ERK/STAT1 and PKD2 etc.…”

Section: Discussionmentioning

confidence: 99%

“…In another study, it was shown that PD-L1 expression could induce epithelial-to-mesenchymal transition in renal cell carcinoma by activating the transcription factor SREBP-1c [22]. Notably, the survival analysis in the TCGA database confirmed that prognoses were better for PD-L1 + /EMT -patients than for PD-L1 + /EMT + patients with human head and neck squamous cell carcinoma [23]. In our previously published studies, we have separately identified PD-L1 expression and EMT as important prognostic factors in human esophageal cancer [24,25].…”

Section: Introductionmentioning

confidence: 96%

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

Chen

Xiong

et al. 2017

Cell Physiol Biochem

100

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Background/Aims: PD-L1 (Programmed cell death 1 ligand 1, PD-L1), an essential immune checkpoint molecule in the tumor microenvironment, is an important target for cancer immunotherapy. We have previously reported that its expression in human gastric and esophageal cancer tissues is significantly associated with cancer progression and patients' postoperative prognoses. Its expression in cancer cells is well known to inhibit the T cellmediated anti-tumor response, and this mechanism of action has been targeted for cancer immunotherapy. As of now, the autonomous effect of PD-L1 on cancer cells is not well understood, thus our present study aimed to examine the role of PD-L1 intervention in cellular biological functions, especially epithelial to mesenchymal transition (EMT), of the human esophageal cancer cell line, Eca-109 cells. Methods: Immunohistochemistry assay was used to investigate the correlation between expression of PD-L1 and EMT markers in human esophageal cancer tissues. Intervention of PD-L1 by using RNAi and over-expression methods were used to study the role of PD-L1 in regulation of biological behaviors and EMT in Eca-109 cells. Results: Our clinical and pathological data demonstrated that tumor samples in the EMT positive subgroup had higher PD-L1 expression than those in the EMT negative subgroup. By manipulating PD-L1 expression in Eca-109 cells either through ablation or overexpression of wild type and the cytoplasmic domain-truncated mutant, we demonstrated that PD-L1 expression significantly promoted the cell viability, migration and EMT phenotype. Furthermore, our study also indicated that PD-1 fusion protein mediated stimulation of PD-L1 and the cytoplasmic domain of PD-L1 played a critical role in promoting EMT phenotype of Eca-109 cells, thereby suggesting that PD-1 receptor usually by triggering the reverse signaling can effect PD-L1 mediated regulation of esophageal cancer cell response. Conclusion: Our present study reveals a tumor cell-autonomous role of PD-L1 signaling in promoting EMT in human esophageal cancer.L. Chen and Y. Xiong contributed equally to this work.

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“…For example, Hwu and colleagues have recently shown that tumor loss of PTEN in melanoma leads to increased inhibition of a T-cell mediated tumor response, with PI3 kinase inhibition at least partially reversing this phenomenon(13). Moreover, the epithelial to mesenchymal transition (EMT) has been linked to upregulation of immune checkpoints such as PD-L1(14,15). As EMT has been linked to both Axl and PI3 kinase activation as well as radiation resistance, it is possible that these signaling cascades may be driving both intrinsic radioresistance as well as inhibition of the tumor immune response necessary for radioresponse(16–18)…”

Section: Introductionmentioning

confidence: 99%

Integrative Analysis Identifies a Novel AXL–PI3 Kinase–PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer

Skinner

Giri

Yang

et al. 2017

Clinical Cancer Research

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Purpose The primary cause of death due to head and neck squamous cell carcinoma (HNSCC) is local treatment failure. The goal of this study was to examine this phenomenon using an unbiased approach. Experimental design We utilized HPV-negative cell lines rendered radiation resistant (RR) via repeated exposure to radiation, a panel of HPV-negative HNSCC cell lines and three cohorts of HPV-negative HNSCC tumors (n=68, 97, & 114) from patients treated with radiotherapy and subjected to genomic, transcriptomic and proteomic analysis. Results RR cell lines exhibited up-regulation of several proteins compared to controls, including increased activation of Axl and PI3 kinase signaling as well as increased expression of PD-L1. Additionally, inhibition of either Axl or PI3 kinase led to decreased PD-L1 expression. When clinical samples were subjected to RPPA and mRNA expression analysis in separate cohorts, PD-L1 was correlated with both Axl and PI3K signaling as well as dramatically associated with local failure following radiotherapy. This finding was confirmed examining a third cohort using immunohistochemistry. Indeed, tumors with high expression of PD-L1 had failure rates following radiotherapy of 60%, 70% and 50% compared to 20%, 25% and 20% in the PD-L1 low expression group (p=0.01, 1.9×10−3 and 9×10−4 respectively). This finding remained significant on multivariate analysis in all groups. Additionally, those patients with PD-L1 low/CD8+TILs high had no local failure or death due to disease (p=5×10−4 and p=4×10−4 respectively). Conclusions Taken together, our data point to a targetable Axl-PI3 kinase-PD-L1 axis that is highly associated with radiation resistance.

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PD-L1 expression is associated with epithelial-mesenchymal transition in head and neck squamous cell carcinoma

Cited by 135 publications

References 54 publications

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

Integrative Analysis Identifies a Novel AXL–PI3 Kinase–PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer

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