Uncovering prognostic architecture of response to immunotherapy in H. pylori infection associated gastric cancer by single-cell transcriptomic analysis

Most gastric cancer (GC) worldwide is ascribed to Helicobacter pylori (H. pylori) infection, which have a detrimental effect on the immunotherapy efficacy, while the key cell players and molecular mechanism associated with GC immunotherapies were rarely described. Herein, we performed comprehensive single-cell-transcriptome analysis of nine GC with current H. pylori-infection (HpGC), three GC with previous H. pylori-infection (ex-HpGC), six GC without H. pylori-infection (non-HpGC), and six healthy controls (HC). HpGC and ex-HpGC were enriched with VEGFA+ angiogenic-tumor-associated-macrophages (Angio-TAM) and IL11/IL24+ inflammatory CAF (iCAF), importantly, iCAFs promoted tumor angiogenesis and immune suppression by interacting with Angio-TAM through VEGFA/B-VEGFR1 and TIGIT+ suppressive T cells through NECTIN2-TIGIT pathway, which is promising target for cancer immunotherapy. Integrated analysis of scRNA and immunotherapy dataset demonstrated the iCAF abundance and angiogenic signature could predict poor GC immunotherapy outcomes. Together, our results delineated the role of H. pylori-infection in GC development, tumor microenvironment regulation, and immunotherapy response.