CAF-macrophage crosstalk in tumour microenvironments governs the response to immune checkpoint blockade in gastric cancer peritoneal metastases

作者：Yuanfang Li, Yongqiang Zheng, Jiaqian Huang, Run‐Cong Nie, Qi‐Nian Wu, Zhijun Zuo, Shuqiang Yuan, Kai Yu, Chengcai Liang, Yi‐Qian Pan, Bai-Wei Zhao, Yuhong Xu, Qihua Zhang, Yashang Zheng, Junquan Chen, Zhao-Lei Zeng, Wei Wei, Zexian Liu, Rui-Hua Xu, Hui Luo · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2024-333617 · 被引用次数：137 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Cancer Cells and Metastasis

Background Peritoneal metastasis is the most common metastasis pattern of gastric cancer. Patients with gastric cancer peritoneal metastasis (GCPM) have a poor prognosis and respond poorly to conventional treatments. Recently, immune checkpoint blockade (ICB) has demonstrated favourable efficacy in the treatment of GCPM. Stratification of best responders and elucidation of resistance mechanisms of ICB therapies are highly important and remain major clinical challenges. Design We performed a phase II trial involving patients with GCPM treated with ICB (sintilimab) combined with chemotherapy. The samples of primary tumours, GCPMs and peripheral blood from patients were collected for single-cell sequencing to comprehensively interpret the tumour microenvironment of GCPM and its impacts on immunotherapy efficacy. Results The GCPM ecosystem coordinates a unique immunosuppressive pattern distinct from that of primary GC, which is dominated by a stroma-myeloid niche composed of SPP1+tumour-associated macrophages (TAMs) and Thrombospondin 2 (THBS2)+matrix cancer-associated fibroblasts (mCAFs). Consequently, this stroma-myeloid crosstalk is the major mediator of ICB resistance in patients with GCPM. Mechanistically, the accumulated THBS2+mCAFs facilitate the recruitment of peritoneum-specific tissue-resident macrophages and their transformation into SPP1+TAMs via the complement C3 and its receptor C3a receptor 1 (C3AR1), thereby forming a protumoral stroma-myeloid niche. Blocking the ...