Exploring the Immune Microenvironment for Predicting Immunotherapy Efficacy in Epstein-Barr Virus-Associated Gastric Cancer

Epstein-Barr virus-associated gastric cancer (EBVaGC) represents an immunogenic subtype of gastric cancer. However, the effectiveness of anti-PD1 agents in EBVaGC remains uncertain, and reliable predictive biomarkers are currently unavailable. Patients with metastatic EBVaGC (n=12) who received anti-PD1 therapy were included. Histologic subtypes were assessed on hematoxylin and eosin-stained slides; PD-L1 expression was evaluated using conventional immunohistochemistry; the immune microenvironment was further characterized by multiplex immunohistochemistry; and all findings were correlated with response to anti-PD1 therapy. Treatment response varied significantly according to the histologic immune classification of EBVaGCs ( P =0.027). A response to treatment was observed in 71.4% (5/7) of carcinomas with Crohn disease-like reactions, whereas no response was observed in conventional adenocarcinomas (0/5). No significant difference was found in the PD-L1 combined positive score between responders and nonresponders, despite a trend toward higher scores in responders ( P =0.081). Quantitative expression measurements using multiplex immunohistochemistry revealed different tumor microenvironments between responders and nonresponders. Higher numbers of PD-L1 + cells ( P =0.048), CD8 + /PD-L1 + cells ( P =0.029), CD4 + cells ( P =0.048), and CD4 + /FOXP3 + cells ( P =0.005) were observed in responders compared with nonresponders. In the tumor area, a higher number of CK + /PD-L1 + cells was observed in responders ( P =0.038). The immune microenvironment was found to influence the response to immunotherapy in EBVaGC. Detailed characterization of the immune microenvironment may enhance the selection of patients with EBVaGCs likely to respond to immunotherapy.