A critical role of epithelial MHCII in initiation of autoimmune tumorigenesis and sustaining premalignancy growth in the stomach

Abstract

Autoimmunity is emerging as a new etiology for early-onset gastric cancer (GC). However, it remains unclear what molecular pathways drive the initiation and progression of autoimmune tumorigenesis. Given that Major Histocompatibility Complex Class II (MHCII) is the strongest genetic risk factor for many autoimmune diseases, we hypothesized that MHCII-mediated autoantigen presentation drives tumorigenic differentiation of epithelial cells. Here we show that epithelial MHCII, rather than MHCII from immune cells, plays an essential role in the initiation of autoimmunity-driven tumorigenic differentiation of gastric epithelial cells, which was characterized by increased expression of cancer-associated markers with immune-evasive and stem-like features that potentiate premalignant progression. In addition, we show that early gastric premalignancy is reversible upon the removal of epithelial MHCII. This study reveals that epithelial MHCII antigen presentation is essential in the early stages of autoimmune-driven gastric tumorigenesis and highlight epithelial MHCII as a potential biomarker or therapeutic target in early interventions of autoimmunity-driven cancer development.