A critical role of epithelial MHCII in initiation of autoimmune tumorigenesis and sustaining premalignancy growth in the stomach 2300319

Abstract

Abstract Introduction Autoimmunity is emerging as a new etiology for early-onset gastric cancer (GC), especially in young women, but 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 hypothesize that MHCII-mediated autoantigen presentation drives tumorigenic differentiation of epithelial cells. Using an autoimmune gastric tumorigenesis model, we examined how MHC II-mediated presentation of autoantigens by hematopoietic or non-hematopoietic compartments may drive the initiation and progression of gastric premalignancy. Methods Rag knockout mice carrying a conditional MHCII deletion or lacking MHCII, or H2DM, were adoptively transferred with splenocytes from CTLA4KD mice, a model of autoimmunity-driven tumorigenesis that mimics human CTLA4 insufficiency and GC risk. Hematopoietic and nonhematopoietic compartments within the stomach were profiled using 40-color spectral flow cytometry. Histopathological evaluation was performed to assess inflammatory and premalignant lesions. Results 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, but not advanced, gastric premalignancy is reversible upon the removal of epithelial MHCII. Conclusion These results reveal 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. Funding Source National Cancer Institute (R01CA245673) and the Sylvester Comprehensive Cancer Center Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)