<em>MiR-155</em> driven loss of ICOSL and SOCS1 in EBV+ gastric cancers renders \ abundant cytotoxic T cells ineffective, enabling immune evasion

Poorly differentiated gastric carcinomas (PDGC) can be further subdivided into Epstein-Barr virus (EBV) positive (+) and EBV-negative (-) subtypes. EBV infection induces miR-155 expression. miR-155 targets ICOSL, a critical immune checkpoint. This study was done to compare the EBV+ and EBV- gastric cancers for their mechanisms of tumor rejection and how EBV-induced oncogenic miR-155 controls these events. For this, we interrogated PDGC samples for EBV status (by staining for EBV encoded factors), paralleled by CD8, PDL1, PD1, ICOSL, ICOS, MHC-I, SOCS1, and miR-155. We found that, despite the similar histological patterns of the PDGC cancer cells, EBV-driven induction of miR-155 suppresses SOCS1 expression, resulting in intense cytotoxic T-cell infiltration, but also loss of the other miR-155 target, ICOSL, making tumor cells invisible to the surrounding intense T cell infiltration. Conversely, EBV-negative tumors retain ICOSL/SOCS1 expression, but exhibit minimal T-cell infiltration, partly due to high SOCS1 expression, preventing immune-mediated clearance. Overall, our data indicates that SOCS1 expression, regulated by EBV-induced miR-155, along with ICOSL status determines whether tumors attract T cells and whether those T cells can effectively eradicate cancer cells.