Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+ T cells

Leng, Cathryn; Li, Yin; Qin, Jianjun; Ma, Jun; Liu, Xianben; Cui, Yingying; Sun, Haibo; Wang, Zongfei; Hua, Xionghuai; Yu, Yonghao; Li, Haomiao; Zhang, Jun; Zheng, Yan; Wang, Wei; Zhu, Junwei; Wang, Qiu-ming

doi:10.3892/or.2015.4435

Cited by 67 publications

(60 citation statements)

References 50 publications

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“…The importance of PD-L1 in tumor development is demonstrated by its overexpression in a wide range of solid tumors. In ESCC, it has previously been reported that 18.9% to 79.7% of ESCC tumors are PD-L1 positive [21], [22], [23], [24], [25]. In this study, we demonstrate that 21% of the tumors are PD-L1 positive among the patients with ESCC in Hong Kong.…”

Section: Discussionsupporting

confidence: 57%

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: 57%

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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“…In the present study, patients with PD‐L1 positive expression had significantly poorer prognosis than those with negative expression. A previous study reported that prognosis was not related to PD‐L2 expression in ESCC . Our previous study reported that among patients with high expression of HLA class I, high PD‐L1 expression was correlated with significantly poorer RFS and OS in ESCC .…”

Section: Discussionmentioning

confidence: 86%

Programmed death‐ligand 1 expression at tumor invasive front is associated with epithelial‐mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma

et al. 2017

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Programmed death‐ligand 1 (PD‐L1) plays a crucial role in the host immune system in cancer progression. The gene promoter region of PD‐L1 also contains a binding site for ZEB1, a transcription factor related to epithelial‐mesenchymal transition (EMT). The purpose of this study was to clarify the relationship between PD‐L1 and EMT and its clinical importance in esophageal squamous cell carcinoma (ESCC). PD‐L1 and ZEB1 expression at the tumor invasive front was examined by immunohistochemistry in resected specimens from 90 patients with ESCC who underwent surgery without preoperative therapy, and their expression and clinicopathological factors were compared. ZEB1 and PD‐L1 expression was determined in TE8 cells, which demonstrate the EMT phenotype, following ZEB1 knockdown by siZEB1. TE5, TE6 and TE11 cells with non‐EMT phenotype were also used for studies of TGF‐β1‐dependent EMT induction and ZEB1 and PD‐L1 expression. In cases of high PD‐L1 expression at the invasive front, significantly greater depth of tumor invasion, EMT, and less CD8+ lymphocyte infiltration were observed. High PD‐L1 expression was also associated with worse overall and relapse‐free survival. A correlation was observed between PD‐L1 and ZEB1 expression. In TE8 cells, siZEB1 suppressed PD‐L1 and promoted E‐cadherin mRNA and protein expression. TGF‐β1 induced EMT and surface expression of PD‐L1 in TE5, TE6 and TE11 cell lines. PD‐L1 expression at the ESCC invasive front was related to ZEB1 expression, EMT and poor prognosis. We suggest that a cooperative mechanism bridging between tumor immune avoidance and EMT contributes to tumor malignancy in ESCC.

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“…[23][24][25][33][34][35][36][37][38][39][40] All these events are necessary to trigger antigen-specific CTLs (CD3 C CD8 C ), able to recognize and destroy tumor cells presenting altered and/or overexpressed molecular structures recognized as tumor-associated antigens. 41,42 On these bases, several studies in PC patients have investigated, with contrasting results, the prognostic role of the basal inflammatory status and lymphocytes density in the primary tumor. [43][44][45] However, all these studies are limited as they have been performed on elderly patients with bone metastases, who had undergone several years of hormonemanipulation and more or less severe prostate-cancer associated co-morbidities, all together potentially affecting the immune response.…”

Section: Discussionmentioning

confidence: 99%

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

Nardone

Botta

Caraglia

et al. 2016

Cancer Biology & Therapy

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Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (C/¡3.93) years, who received salvage radiotherapy with a mean of 69.66 (C/¡ 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (C/¡ 55.82) months, were enrolled in this study. We evaluated, by immunohistochemistry, the intratumoral ( t ) and peripheral stroma ( p ) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3 or PD-1-positive cells on tumor samples taken at the diagnosis ( d ) and relapse times ( R ). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1 C cells. Our analysis revealed that higher CD8 p,RC and lower PD-1 RC TIL scores correlated to a longer bPFS. Higher CD8 p,RC and CCR7 t,RC TIL scores and lower CD45 p,RC and FoxP3 p,RC TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

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Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+ T cells

Cited by 67 publications

References 50 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

Programmed death‐ligand 1 expression at tumor invasive front is associated with epithelial‐mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

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