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

Abstract

Poorly differentiated gastric carcinomas (PDGC) comprise 30% of gastric cancers and are associated with poor prognosis, correlating with tumor size and microvascular invasion. PDGC may be subcategorized as Epstein-Barr virus (EBV)-positive or EBV-negative. Based on prior work with EBV-positive nasopharyngeal carcinomas, we interrogated 33 PDGC samples for EBV DNA/RNA/protein, CD8, PDL1, PD1, Inducible T cell Co-Stimulator Ligand (ICOSL), ICOS, MHC-I, Suppressor of cytokine signaling 1 (SOCS1), and <i>miR-155</i>. The 13 EBV-positive tumors each showed intense PD1, PDL1, and CD8+ T cell responses that were largely absent in EBV-negative tumors. EBV EBER-1/2 RNA strongly colocalized with <i>miR-155</i> in cancer cells with a concomitant loss of ICOSL expression as well as downregulation of cytokine signaling suppressor, SOCS1. In contrast, the 20 EBV-negative PDGCs showed weak to no <i>miR-155</i> expression, with strong ICOSL and SOCS1 expression. On the other hand, the MHC-I expression was lost in both PDGC types. These data suggest that, despite the similar histological patterns of the cancer cells, EBV-driven induction of <i>miR-155</i> suppresses SOCS1 expression, resulting in intense cytotoxic T cell infiltration, but also loss of the other <i>miR-155</i> 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 indicate that SOCS1 expression, regulated by EBV-induced <i>miR-155</i>, along with ICOSL status determines whether tumors attract T cells and whether those T cells can effectively eradicate cancer cells.