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Takehito Uruo, Takaaki Tatsuguchi, Yuki Sugiura, Yoshinori Fukui, A tumor metabolite impacting immunotherapy efficacy: Cholesterol sulfate regulates tumor-immune interactions, Keystone Symposia on "Cancer Immunotherapy: Mechanisms of Response versus Resistance", 2023.03, Tumors constitute an ecosystem of heterogeneous metabolic environments where a variety of metabolites function as intra- and intercellular mediators that affect tumor development. We previously identified that cholesterol sulfate (CS) is an endogenous inhibitor of DOCK2, a Rac activator essential for leukocyte migration and activation. Thereby, local CS production creates immune-evasive/immunosuppressive microenvironments. Many types of human cancers express the SULT2B1 gene, encoding the steroid sulfotransferase SULT2B1b responsible for CS production, and in certain cancers, the gene expression associates with poor prognosis. In colon cancers, level of CS is higher in tumor tissues, and tumor regions with high CS were poorly infiltrated with CD8+ T cells. In syngeneic mouse models, CS-producing cancer cells formed larger tumors in a host-immunity-dependent manner, and exhibited resistance to immunotherapies via antigen-specific T cell transfer and immune-checkpoint blockade. A novel SULT2B1b inhibitor we identified counteracted the above phenotypes. Thus, cancer-derived CS is a key mediator of tumor-immune interactions, and CS/SULT2B1b may be a potential target for enhancing the efficacy of immunotherapies.. |
