TIM3+ Tumor Associated M2 Macrophages Impair Antitumor T Cell Immunity and Promote Gastric Cancer Progression and Peritoneal Metastasis

Abstract

Peritoneal metastases (PM) are the leading cause of cancer-related death in gastric cancer (GC) patients with survival typically < 9 months. Here, we demonstrate that TIM3 and its ligands are increased along the GC continuum and associated with poor survival. Integrated omics analyses and functional studies revealed highly enriched TIM3 in CD163+ tumor associated M2 immunosuppressive macrophages significantly promote tumor cell invasion and tumor growth in vivo, while TIM3 depletion in macrophages reduced tumor cell malignant attributes and increased T cell immunity from PBMCs or CD45+ immune cells of malignant ascites in co-culture system. By cytokine and kinase arrays, we discovered that depletion of TIM3 in macrophages reduced the production of notable secretome of cytokines/chemokines from M2 macrophages; and the protumor function of TIM3+ macrophages rely on the p90RSK1/2/CCL20 axis. Finally, we reveal that TIM3 blockage or genetic KO had superior antitumor activity in combination with anti-PD1 immunotherapy and mitomycin C (MMC) chemotherapy. Together, this study uncovers an important role for TIM3 in tumor associated M2 macrophages and underscores the potential of TIM3 blockage in GC patients with PM. Statement of significanceIn this study, we show TIM3 increases along GC continuum, and highly enriched on tumor associated M2 macrophages that fuel tumor growth; and suppress T cell function via p90RSK1/2/CCL20 axis. TIM3 depletion restores T-cell immunity and curbs tumor growth. TIM3 blockade combined with anti-PD1 and mitomycin C provide a novel therapeutic strategy for GC patients with PM.