Glycosylation-driven programs control the immunosuppressive and pro-tumorigenic activities of small extracellular vesicles 4450

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Abstract Description Breast cancer (BC) and prostate cancer (PCa) metastasis are supported by small extracellular vesicles (EVs) released by regulatory myeloid (mEVs) and tumor (tEVs) cells. Galectin 1 (Gal1) is an endogenous lectin that binds to N- and O-glycans. This binding can be modulated by α2,6-linked sialylation, mediated by ST6GAL1. We propose that Gal1 and ST6GAL1 control EV-driven immunosuppression, shaping immune responses and metastasis. We found that Gal1 binds to the CD18/CD11b complex on myeloid cells, enhancing T-cell suppression by upregulating PD-L1, IDO and VISTA, increasing reactive oxygen species, nitric oxide and IL-10/IL-27 secretion. Activation by Gal1 also alters the protein and metabolite cargo of mEVs, which further suppress T-cell responses. Moreover, mEVs upregulate metastatic potential of BC (4T1) cells in vivo and support metastasis in the lung. Gal1 in the cargo of 4T1 tEVs confers them the ability to suppress T- and B-cell responses. In our PCa context, mEVs carry the membrane-bound form of ST6GAL1. We classified the metastatic PCa cell lines PC3, DU145 and C4-2B as low, moderate and high expressors of both membrane-bound and soluble ST6GAL1 forms. While PC3 tEVs contain both ST6GAL1 forms, DU145 tEVs carry only the soluble form, and C4-2B tEVs, a bone metastatic cell line, retain only the membrane-bound form. tEVs transfer membrane-bound ST6GAL1 to recipient cells. Thus, glycosylation programs control EV-mediated myeloid-driven immunosuppression and metastasis. Funding Sources Supported by DOD W81XWH2210826 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

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