CAF‒macrophage crosstalk in tumor microenvironments governs the response to immune checkpoint blockade in gastric cancer peritoneal metastases
Description
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 favorable 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 tumors, GCPMs, and peripheral blood from patients were collected for single-cell sequencing to comprehensively interpret the tumor microenvironment of GCPM and its impact on immunotherapy efficacy. Results: The GCPM coordinates a unique immunosuppressive pattern distinct from that of primary GC, which is dominated by a stroma-myeloid niche composed of SPP1+ tumor-associated macrophages (TAMs) and THBS2+ matrix cancer-associated fibroblasts (mCAFs). Consequently, this stroma–myeloid crosstalk is the major mediator of ICB resistance in patients with GCPMs. 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 C3‒C3AR1 axis disrupts the stroma–myeloid crosstalk and thereby significantly improves the benefits of ICB in in vivo models. Conclusion: Our findings provide a new molecular portrait of cell compositions associated with ICB resistance in patients with GCPMs and aid in the prioritization of therapeutic candidates to potentiate immunotherapy.