Metastasis associated macrophages drive immunosuppression and fibrosis in gastric peritoneal carcinomatosis

Gastric cancer peritoneal metastasis (GC-PM) remains a lethal disease with 5-6% overall survival. Macrophages are the predominant antigen presenting cells in the peritoneum initiating innate and adaptive responses. Thus, macrophage-based therapies may be an important avenue for immune based therapeutic strategies. However, the role and regulators of metastasis associated macrophages (MAMs) in GC-PM remain uncertain. Comparative transcriptomic analysis of malignant ascites and solid peritoneal tumor implants demonstrated that MAMs are a predominant cell type in the tumor microenvironment. Using syngeneic murine models of gastric carcinomatosis, we observed that targeted macrophage depletion restricted tumor growth as evidenced by 80% reduction in tumor weights, total body tumor volume, number of nodules, and malignant bowel obstruction. Bulk RNA sequencing of the malignant ascites demonstrated upregulation of pathways associated with T cell activation, differentiation and proliferation with macrophage depletion. In addition, bulk RNA sequencing of the macrophage-depleted tumor tissue showed downregulation of pro-fibrotic genes Col1a1, Fgf2 and Itgb1 compared with controls. Multiplex cytokine array revealed inhibition of immunosuppressive chemokines IL-10, IL-6 and CXCL1 with macrophage depletion. Functionally, co-cultured isolated MAMs isolated from malignant ascites and tumor nodules inhibited naïve polyclonal CD4+ T cell activation ex-vivo. Taken together, we elucidate dual mechanisms by which metastasis associated macrophages promote oncogenesis through altering adaptive anti-tumor immunity and promoting fibrosis in gastric peritoneal metastasis. Future studies will identify macrophage subsets that can be targeted for potential therapies.