TREM1 Blockade Reprograms Tumor-Associated Macrophages and Improves Anti-PD-1 Efficacy in Gastric Cancer.

OBJECTIVE: The objective response rate of immune checkpoint inhibitors in patients with gastric cancer is limited. Targeting specific subtypes of macrophages holds promise for expanding the potential population sensitive to immune checkpoint inhibitors. This study aims to evaluate the key role of TREM1+tumor-associated macrophages (TAMs) in regulating antitumor immunity. METHODS AND ANALYSIS: This study included four cohorts, consisting of three tumor microarrays and transcriptomic data from the Cancer Genome Atlas (TCGA). The association between TREM1+TAMs and clinical outcomes and genomic characteristics was analyzed. Freshly resected tumor tissues were cultured in vitro to assess the potential therapeutic effect of blockade of TREM1 in gastric cancer. RESULTS: High TREM1+TAMs level indicates poor prognosis and tumor progression in patients with resectable gastric cancer. TREM1+TAMs infiltration is negatively associated with objective response rate to immune checkpoint inhibitors in patients with advanced gastric cancer. TREM1+TAMs lead to dysfunction of CD8+T cells by expressing PD-L1 and TGFβ. Finally, we show that inhibiting TREM1+TAMs promotes antitumor immunity in gastric cancer. CONCLUSIONS: TREM1+TAMs infiltration was an independent prognostic predictor in patients with gastric cancer. TREM1+TAMs contributed to the immune escape by displaying PD-L1 and TGFβ. Blockade of TREM1 drove antitumor response, providing potential therapeutic effects for gastric cancer patients.