Siglec-7/9 are glyco-immune checkpoints for enhanced immunotherapy in prostate cancer

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Presentation Time: 02:30 PM - 02:45 PM
Abstract ID: 5187 - B

Presenting Author:
Ru Wen , Postdoc at Stanford Univ. Sch. of Med.

Abstract:

Immune checkpoint inhibitor-based therapies have revolutionized cancer treatment, however, their efficacy in prostate cancer remains limited. Sialic acid-binding immunoglobulin-type lectins (Siglecs) is a family of immunoglobulin-type lectins that bind to sialic acids. TCGA analysis reveals high expression of Siglec-7/9 in tumor-infiltrating immune cells in prostate cancer, and this heightened expression is correlated with worse outcomes. Elevated levels of Siglec-7/9 ligands were found in prostate cancer tissues compared to adjacent normal tissues. Flow cytometry demonstrates the expression of Siglec-7/9 ligands and sialic acids in prostate cancer cells. Increased sialylation was found in tumor tissues by proteomic analysis. Disrupting Siglec-7/9 interactions suppresses immune cell-mediated cytotoxicity. Anti-Siglec-7/9 treatment inhibits PC3 and 22Rv1 tumor growth in vivo. Further IHC analysis reveals reduced proliferation, increased apoptosis, and enhanced immune cell infiltration in groups treated with anti-Siglec-7/9 compared to those treated with isotype controls. CRISPR screen and mass spectrometry identify CD59 as a potential Siglec-9 ligand, a finding confirmed by Siglec-9 Fc pull-down assay. CD59 knockout enhances T cell-mediated cytotoxicity to prostate cancer cells. These findings underscore the potential of targeting Siglec-7/9 immune checkpoints to develop novel immune checkpoint inhibitor-based drugs for prostate cancer.