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Abstract
Background This study aims to elucidate the transition during the multi-stage progression of gastric lesions and to investigate the impact of H.pylori infection (HPI) on the immune microenvironment during gastric carcinogenesis.
Methods Our study incorporated an in-house dataset with three public scRNA-seq and scTCR/BCR datasets. An atlas comprising over 100,000 high-quality cells from 52 samples spanning the entire spectrum during gastric carcinogenesis, including superficial or chronic atrophic gastritis (SG/CAG), intestinal dysplasia (IM), dysplasia (DYS), gastric cancer (GC), and cancer-adjacent tissue (GC_ADJ), was generated (IDDF2024-ABS-0274 Figure 1. Single-cell RNA landscape profiling of multi-stage gastric lesions). HPI was determined through 13C-urea breath tests (13CUBT) in conjunction with serum antibody assays.
Results Our findings revealed the dynamic microenvironment landscape throughout the multi-stage progression from gastritis to gastric cancer. We investigated the role of HPI in this process, focusing on its effects via epithelial-immune interactions. Notably, epithelial components exhibited a gastric-intestinal phenotypic shift (IDDF2024-ABS-0274 Figure 2. Profiling of epithelial cells). The intestinal metaplasia (IM) stem-like cells, derived from the isthmus stem-like cells, were situated in a crucial niche in determining the direction of differentiation. As these cells transitioned towards immature enterocytes, a malignant phenotype emerged. Additionally, we observed that HPI was associated with elevated levels of CXCL/CCL chemokines, TNF signaling activity, and MHC-II molecule expression in gland mucous cells (GMCs), parietal cells, and IM cells, indicating an immune-activated state. This immune activation was further characterized by the clonal expansion of CD8+ T cells, accompanied by the infiltration of CD4+ follicular helper T cells (Tfh) and B cells to combat the infection (IDDF2024-ABS-0274 Figure 3. Profiling of T&NK cells). Furthermore, as the disease stage progressed, a decline in CD8+ tissue-resident memory cells (Trm), and a dominance of CD4+ FOXP3 + regulatory T cells (Treg) was noted, suggesting a gradual shift from an immune-activated to an immunosuppressive landscape. Intriguingly, even in the premalignant stages with HPI, infiltration of Treg cells already existed, potentially contributing to the chronic inflammation and the establishment of a pro-cancerous microenvironment.
Single-cell RNA landscape profiling of multi-stage gastric lesions.
Profiling of epithelial cells.
Profiling of T&NK cells.
Conclusions A pro-cancerous microenvironment gradually emerges during the multi-stage gastric carcinogenesis, with HPI as a pivotal modulating factor.