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

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-Ll 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-Ll 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.