Targeting Siglec-10/a3ß1 Integrin Interactions Enhances Macrophage-Mediated Phagocytosis of Pancreatic Cancer

Tumor-associated macrophages (TAMs) in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) exhibit immunosuppressive phenotypes and impaired phagocytic activity, facilitating tumor progression and immune evasion. Here, we identify integrin a3ß1, composed of ITGA3 and ITGB1 subunits, as a sialylated glycoprotein ligand for Siglec-10, an inhibitory glyco-immune checkpoint receptor highly expressed on TAMs in PDAC. The interaction between Siglec-10 on TAMs and a3ß1 on PDAC cells suppresses macrophage-mediated phagocytosis, thereby promoting immune evasion. Consistently, disrupting Siglec-10 interactions with monoclonal antibodies significantly enhances macrophage phagocytosis of PDAC cells and alleviates myeloid cell-mediated inhibition of T cell proliferation and activation in vitro. In both a PDAC xenograft mouse model engrafted with human macrophages and a human Siglec-10 transgenic mouse model, targeting Siglec-10 with monoclonal antibodies reduces PDAC tumor growth. These findings suggest that the Siglec-10 interactions are key mediators of TAM-driven immune evasion in PDAC and highlight the therapeutic potential of targeting these interactions to restore anti-tumor immunity in PDAC. Overall design: RNA-seq profiling of tumor-associated macrophages (TAMs) isolated from NSG mice co-injected with human TAMs and either isotype control or Siglec-10 antibody.