Biochemical and biophysical research communications | VOL. 609
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Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity.

Publication Date Jun 18, 2022

Abstract

Effective cancer immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute special microenvironments that exclude T cells and resist immunotherapy. Cholesterol sulfate (CS) is a product of sulfotransferase SULT2B1b and acts as an endogenous inhibitor of DOCK2, a Rac activator essential for migration and activation of lymphocytes. We have recently shown that cancer-derived CS prevents tumor infiltration by effector T cells. Therefore, SULT2B1b may be a therapeutic target to dampen CS-mediated immune evasion. Here, we identified 3β-hydroxy-5-cholenoic acid (3β-OH-5-Chln) as a cell-active inhibitor of SULT2B1b. 3β-OH-5-Chln inhibited the cholesterol sulfotransferase activity of SULT2B1b invitro and suppressed CS production from cancer cells expressing SULT2B1b. Invivo administration of 3β-OH-5-Chln locally reduced CS level in murine CS-producing tumors and increased infiltration of CD8+ T cells. When combined with immune checkpoint blockade or antigen-specific T cell transfer, 3β-OH-5-Chln suppressed the growth of CS-producing tumors. These results demonstrate that pharmacological inhibition of SULT2B1b can promote antitumor immunity through suppressing CS-mediated T cell exclusion.

Concepts
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Cholesterol Sulfate
Immune Checkpoint Blockade
Activation Of Lymphocytes
Cell Transfer
Migration Of Lymphocytes
Cancer Cells
Effective Immunotherapy
Murine Tumors
Growth Of Tumors
Cholesterol Sulfotransferase Activity

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