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Orchestration of immune checkpoints in tumor immune contexture and their prognostic significance in esophageal squamous cell carcinoma

Authors Zhao JJ, Zhou ZQ, Wang P, Chen CL, Liu Y, Pan QZ, Zhu Q, Tang Y, Weng DS, Xia JC

Received 30 July 2018

Accepted for publication 30 October 2018

Published 28 November 2018 Volume 2018:10 Pages 6457—6468


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr Xueqiong Zhu

Jing-Jing Zhao,1,2,* Zi-Qi Zhou,1,2,* Peng Wang,3,4,* Chang-Long Chen,1,2 Yuan Liu,1,2 Qiu-Zhong Pan,1,2 Qian Zhu,1,2 Yan Tang,1,2 De-Sheng Weng,1,2 Jian-Chuan Xia1,2

1Department of Experimental Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; 2Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, China; 3Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; 4Department of Medical Research, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

*These authors contributed equally to this work

Introduction: Esophageal squamous cell carcinoma (ESCC) develops in a background of chronic inflammation; therefore, it is a promising candidate for treatment by immunotherapy. Although tumor immunity is critically involved in tumor growth and metastasis in ESCC, important gaps exist in our understanding of its immune microenvironment. This study aimed to investigate the expression and prognostic significance of immune checkpoint proteins in ESCC and the associated T-cell densities.
Materials and methods: We investigated the infiltration of CD8+ T cells and the expressions of immune checkpoint proteins (PD-1, TIGIT, PD-L1, and PD-L2) in 154 primary ESCC patients by immunohistochemistry. The correlation of immune checkpoint proteins’ expression and clinical outcomes was determined by Kaplan–Meier test and multivariate Cox regression analysis.
Results: PD-L1 and PD-L2 expression were detected in 45.5 and 59.7% of the ESCC samples, respectively. The high densities of PD-1+ and TIGIT+ tumor-infiltrating lymphocytes (TILs) were expressed in 47.4 and 49.4% of the ESCC patients, respectively. The number of PD-1+ TILs was significantly positively correlated with CD8+ TILs (P<0.001). Cases displaying high PD-L1 expression exhibited consistently high CD8+ T-cell infiltration (P=0.0157). Increased numbers of PD-1+ and TIGIT+ TILs alone or both, as well as PD-L1 and PD-L2 expression alone or both, were significantly and associated with a shorter overall survival among these patients. The combined analysis of the expression of PD-1, TIGIT, PD-L1, and PD-L2 found that a group of patients with PD-1+/TIGIT+ TILs and PD-L1- and/or PD-L2-positive tumor cells had the worst prognosis in primary ESCC.
Conclusion: These immune profiles of checkpoint proteins expression should guide the selection of ESCC patients to receive suitable immunotherapies.

Keywords: biomarker, PD-1, prognostic significance, immune microenvironment, tumor-infiltrating lymphocytes

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