Longer survival of Helicobacter pylori positive gastric cancer patients is associated with a more active T cell immune response as revealed by single-cell sequencing

Background: The effect of Helicobacter pylori (H. pylori) status on survival for gastric cancer remains unclear. We aimed to elucidate the molecular heterogeneity of tumour-infiltrating T cells in gastric cancer with different H. pylori infection status.Methods: We conducted a prognostic analysis of 488 gastric cancer patients and performed single-cell RNA sequencing (scRNA-seq) analysis on 18,717 T cells from 6 tumour samples with or without H. pylori infection. Analysis results were validated using histological assays and bulk transcriptomic datasets.Results: We confirmed that gastric cancer patients with H. pylori infection had a significantly longer survival time compared to patients with negative H. pylori status (HR=0.74, 95% CI=0.55-0.99, P= 0.045). After unsupervised re-clustering of T cells based on scRNA-seq data, we identified ten CD4+ and twelve CD8+ clusters. Among them, four clusters in CD8+ T cells appeared to exhibit distinct distributions with different H. pylori infection status. One subgroup marked by CXCL13, which contained mostly cells of H. pylori infection and expressed high levels of IFNG, GZMB and low level of PDCD1, was activated by TNFRSF1A-TNF interaction. The developed gene signature was significantly associated with improved patient survival in gastric cancer. The other subgroup specifically expressed immune suppression-related genes AREG and PTGER2, was almost exclusively populated with cells without H. pylori infection. High PTGER2 expression was significantly associated with worse prognosis with high CD8 expression.Conclusion: Our results shed light into the mechanisms underlying the target cell dependent T cell responses induced by H. pylori, which will provide assistance for precision treatment and prognosis.