Molecular cancer · 2025
Spatial and functional dissection of cancer-associated fibroblasts-mediated immune modulation in H. pylori-associated gastric cancer.
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Chen Bonan, Tang Hongzhen, Zheng Xiaohong, Xie Fuda, Yu Peiyao, Lyu Yang, Feng Tiejun, Wu Jialin, Liu Jingya, Xu Yi, Cheung Alvin H K, Fang Canbin, Wang Zhangding, Wang Shouyu, Cheung Justin Chak Ting, Dong Yujuan, Tian Ruoxi, Zhang Yigan, Lu Cheng, Wong Chi Chun, Yu Jun, Wu William K K, Burgermeister Elke, Tong Man, Zhang Fengbin, Kang Wei, Leung Kam Tong, To Ka Fai
Аннотация
BACKGROUND: Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment, yet their spatial organization and immunomodulatory functions in H. pylori-associated gastric cancer (GC) remain incompletely understood.
METHODS: We profiled formalin-fixed paraffin-embedded (FFPE) tumors from 71 GC patients using spatial transcriptomics and integrated single-cell RNA-seq from three independent cohorts (China, USA, and Singapore). CAF-immune cell colocalization was quantified by neighborhood enrichment and aggregation index score. Ligand-receptor inference and trajectory analysis resolved CAF signaling and state transitions. To delineate post-transcriptional control, ARE-motif scanning and expression correlations were combined with laser-assisted crosslinking and immunoprecipitation sequencing (LACE-seq) to nominate ZFP36 targets. Immune contexture and prognostic associations were evaluated using CIBERSORT-ABS and Kaplan-Meier analyses in The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) cohorts.
RESULTS: We first defined the spatial distributions of the four CAF subtypes reported in prior studies and found that their immune associations varied across histologic and infection-defined GC subtypes. In H. pylori-positive tumors, THBS1⁺ CAFs were spatially enriched near regulatory T cells (Tregs) and were associated with local immunosuppression through WNT5-FZD interactions. In parallel, ZFP36 bound AU-rich elements within the FN1 3' untranslated region (3'UTR), destabilizing FN1 mRNA and thereby diminishing FN1⁺ CAF-mediated cytotoxic T lymphocyte (CTL) activation. Together, these axes promoted Treg accumulation and suppression of CTL activation.
CONCLUSIONS: These findings reveal infection-associated stromal programs that shape the immune landscape in GC and highlight CAF-directed pathways as potential therapeutic targets in H. pylori-associated GC.
METHODS: We profiled formalin-fixed paraffin-embedded (FFPE) tumors from 71 GC patients using spatial transcriptomics and integrated single-cell RNA-seq from three independent cohorts (China, USA, and Singapore). CAF-immune cell colocalization was quantified by neighborhood enrichment and aggregation index score. Ligand-receptor inference and trajectory analysis resolved CAF signaling and state transitions. To delineate post-transcriptional control, ARE-motif scanning and expression correlations were combined with laser-assisted crosslinking and immunoprecipitation sequencing (LACE-seq) to nominate ZFP36 targets. Immune contexture and prognostic associations were evaluated using CIBERSORT-ABS and Kaplan-Meier analyses in The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) cohorts.
RESULTS: We first defined the spatial distributions of the four CAF subtypes reported in prior studies and found that their immune associations varied across histologic and infection-defined GC subtypes. In H. pylori-positive tumors, THBS1⁺ CAFs were spatially enriched near regulatory T cells (Tregs) and were associated with local immunosuppression through WNT5-FZD interactions. In parallel, ZFP36 bound AU-rich elements within the FN1 3' untranslated region (3'UTR), destabilizing FN1 mRNA and thereby diminishing FN1⁺ CAF-mediated cytotoxic T lymphocyte (CTL) activation. Together, these axes promoted Treg accumulation and suppression of CTL activation.
CONCLUSIONS: These findings reveal infection-associated stromal programs that shape the immune landscape in GC and highlight CAF-directed pathways as potential therapeutic targets in H. pylori-associated GC.