Targeting Siglec-10/α3β1 Integrin Interactions Enhances Macrophage-Mediated Phagocytosis of Pancreatic Cancer

Abstract

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 3{beta}1, 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 3{beta}1 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 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. SIGNIFICANCEPancreatic tumor cells exploit integrin 3{beta}1 to engage the immunosuppressive checkpoint receptor Siglec-10 on myeloid cells, driving immune evasion, and antibody-mediated blockade of Siglec-10 restores myeloid cell-mediated anti-PDAC immunity.