Immune Landscape of Epstein-Barr Virus-Associated Gastric Cancer: Analysis From a Western Academic Institution

Introduction: Epstein-Barr virus-associated gastric cancer (EBVaGC) may be a meaningful biomarker for potential benefit from immunotherapy. Further investigation is needed to characterize the immune landscape of EBVaGC. We assessed our institutional frequency of surgically treated EBVaGC and analyzed the immunologic biomarker profile and tumorinfiltrating lymphocyte (TIL) phenotypes of a series of EBVaGC compared to non-EBVaGC cases. Methods: Available tissue samples from all patients with biopsy-confirmed gastric adenocarcinoma who underwent resection with curative intent from 2012 to 2020 at our institution were collected. In situ hybridization was used to assess EBV status; multiplex immunohistochemistry was performed to assess mismatch repair status, Programmed Death-Ligand 1 (PD -L1) expression, and phenotypic characterization of TILs Results: Sixty-eight samples were included in this study. EBVaGC was present in 3/68 (4%) patients. Among all patients, 27/68 (40%) had positive PD -L1 expression; two of three (67%) EBVaGC patients exhibited positive PD -L1 expression. Compared to non-EBVaGC, EBVpositive tumors showed 5-fold to 10-fold higher density of TILs in both tumor and stroma and substantially elevated CD8+ T cell to Tregulatory cell ratio. The memory subtypes of CD8+ and CD4+ T cells were upregulated in EBVaGC tumors and stromal tissue compared to non-EBVaGC. Conclusions: The incidence of surgically resected EBVaGC at our center was 4%. EBVaGC tumors harbor elevated levels of TILs, including memory subtypes, within both tumor and tumor-related stroma. Robust TIL presence and upregulated PD -L1 positivity in EBVaGC may portend promising responses to immunotherapy agents. Further investigation into routine EBV testing and TIL phenotype of patients with gastric cancer to predict response to immunotherapy may be warranted.