IDDF2024-ABS-0274 From gastritis to gastric cancer: a multi-stage landscape profiling reveals pro-cancerous microenvironment establishment mediated by h.pylori induced epithelial-immune interactions

<h3>Background</h3> This study aims to elucidate the transition during the multi-stage progression of gastric lesions and to investigate the impact of <i>H.pylori</i> infection (HPI) on the immune microenvironment during gastric carcinogenesis. <h3>Methods</h3> 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. <h3>Results</h3> 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&amp;NK cells). Furthermore, as the disease stage progressed, a decline in CD8⁺ tissue-resident memory cells (Trm), and a dominance of CD4⁺<i>FOXP3</i>⁺ 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. <h3>Conclusions</h3> A pro-cancerous microenvironment gradually emerges during the multi-stage gastric carcinogenesis, with HPI as a pivotal modulating factor.