Abstract 7524: Targeting siglec-7/9 glyco-immune checkpoints in prostate cancer for enhanced immune responses and tumor suppression

Abstract Prostate cancer is one of the leading causes of death in men worldwide. Despite significant advancements in the fight against cancer, immune checkpoint inhibitors have limited effectiveness in treating prostate cancer. Evidence shows that disrupting the interactions between Siglec-7/9 and sialic acids can enhance immune responses and effectively inhibit tumor growth in several cancers. However, the understanding of Siglec-7/9-sialic acid interactions in prostate cancer remains limited. Here, we found that tumor-infiltrating immune cells derived from prostate cancer patients exhibited high levels of Siglec-7 and Siglec-9. TCGA data analysis suggests that high levels of Siglec-7/9 are correlated to worse patient survival. Elevated levels of Siglec-7/9 ligands were found in prostate tumor tissues compared to adjacent normal tissues. Prostate cancer cell lines exhibited significant expression levels of Siglec-7 and Siglec-9 ligands, and cell surface sialic acids. Proteomic analysis suggests that increased sialylation was observed in tumor tissues in comparison to adjacent normal tissues. Disrupting interactions between Siglec-7/9 and sialoglycans enhanced T cell-mediated cytotoxicity against prostate cancer cells. Treatment with anti-Siglec-7/9 antibodies effectively suppressed the growth of PC3 and 22Rv1 tumors in a humanized mouse model. Immunohistochemistry analysis of tumor tissues showed that PC3 and 22Rv1 tumors treated with anti-Siglec-7/9 exhibited reduced proliferation, decreased vascularization, increased apoptosis, and enhanced immune cell infiltration. The CRISPR screen and mass spectrometry analysis suggested CD59 as a potential ligand for Siglec-9. Knockout of CD59 in prostate cancer cells decreased their binding activity of Siglec-9-Fc chimera proteins and promoted T cell-mediated killing ability. These findings provide valuable insights into the potential therapeutic strategy of targeting Siglec-7/9 and their ligands for prostate cancer treatment. Citation Format: Ru Wen, G Edward Marti, Jessica Stark, Fernando Jose Garcia Marques, Nick Riley, Abel Bermudez, Hongjuan Zhao, Carolyn Bertozzi, Sharon Pitteri, James Brooks. Targeting siglec-7/9 glyco-immune checkpoints in prostate cancer for enhanced immune responses and tumor suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7524.