Targeting Interactions Between Siglec-10 and α3β1 Integrin Enhances Macrophage-Mediated Phagocytosis of Pancreatic Cancer
Year: 2025
Type: article
Abstract: Tumor-associated macrophages (TAM) in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) exhibit immunosuppressive phenotypes and impaired phagocytic activity, facilitating tumor progression and immune evasion. In this study, we identified integrin α3β1, 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 α3β1 on PDAC cells suppressed macrophage-mediated phagocytosis, thereby promoting immune evasion. Consistently, disrupting Siglec-10 interactions using mAbs significantly enhanced macrophage phagocytosis of PDAC cells and alleviated myeloid cell-mediated inhibition of T-cell proliferation and activation in vitro. In both a xenograft mouse model engrafted with human macrophages and a human Siglec-10 transgenic mouse model, targeting Siglec-10 with mAbs reduced PDAC 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 antitumor immunity. SIGNIFICANCE: Pancreatic tumor cells exploit integrin α3β1 to engage the immunosuppressive checkpoint receptor Siglec-10 on myeloid cells, driving immune evasion, which can be targeted with antibody-mediated blockade of Siglec-10 to restore antitumor immunity.
Source: Cancer Research
Authors: Pratima Saini, Gauri Mirji, S M Shamsul Islam, Lacy M. Simons, Sajad Ahmed Bhat, Amanda P. Bonfanti, Kar Muthumani, Priyesh Agrawal, Joel Cassel, Hsin-Yao Tang, Hiroaki Tateno, Rugang Zhang, Judd F. Hultquist, Rahul S. Shinde, Mohamed Abdel-Mohsen
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, Feinberg School of Medicine, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy, Sialic Acid Modulation of HIV-associated Chronic Inflammaging, Glycomic Modulation of Inflammaging and Immune Functions during HIV Infection, G5500086749, Microbiota-Mediated Bidirectional Interactions Between Alcohol Misuse and Post-COVID-19 Syndrome, Glycomic Modulation of Gut Microbiome During HIV Infection, Host Glycomic Modulation of HIV-associated Neuro-inflammation During Viral Suppression, G7634912203, Characterizing the sources, mechanisms, and translational relevance of microbial TMAO in driving anti-tumor immunity in pancreatic cancer., Advancing Cancer Research through Comprehensive Proteomics and Metabolomics Analyses, Glycomic Modulation of Inflammaging and Immune Functions during HIV Infection, Estrogen's Impact on IgG Glycomic Modulation of Immunity and Inflammation During HIV, Targeting Siglec-9/Sialoglycan Interactions to Enhance NK Functions During HIV Infection, Consolidated Basic Cancer Research Program, Gut Microbiota-Mediated Inflammatory Interactions Between Alcohol Use Disorders and HIV Infection
OpenAlex ID: W4415809980