Downregulation of GSDMB by EBV-encoded miR-BART12-3p suppresses killer lymphocyte-mediated pyroptosis in gastric cancer cells

Abstract

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer (GC) with characteristic clinicopathological and molecular features. EBVaGC exhibits a more extensive lymphocyte infiltration than EBV-negative counterparts, and expresses a range of EBV encoded viral products. However, the interactions between EBV-positive GC cells and immune cells within the tumor microenvironment are not well understood. Herein we found that EBV downregulates GSDMB, an executive molecule of pyroptosis, in EBV-positive GC cells and enables these cells to escape GSDMB cleavage-induced pyroptosis by NK cells and cytotoxic T lymphocytes. The pyroptosis is mainly executed through the full length GSDMB isoform (GSDMB iso3 ) in GC cells. We further found EBV-encoded miR-BART12-3p targets the GSDMB 3’-UTR to downregulate its expression in GC cells. Inhibition of miR-BART12-3p enhances antitumor efficacy of NK cells against EBV-positive GC cells by triggering GSDMB cleavage-induced pyroptosis, as demonstrated both in vitro and in vivo . In conclusion, this study elucidates the molecular mechanism by which EBV downregulates GSDMB to evade immune cell killing, and provides a rationale for combining killer lymphocyte-based therapies with a miR-BART12-3p inhibitor for the treatment of EBVaGC.