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

UNLABELLED: 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 SIGNIFICANCE: In 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.