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Tytuł:
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Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity.
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Autorzy:
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Tatsuguchi T; Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Uruno T; Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. Electronic address: .
Sugiura Y; Department of Biochemistry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Oisaki K; Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo, 113-0033, Japan.
Takaya D; Laboratory for Structure-Based Molecular Design, RIKEN Center for Biosystems Dynamics Research, Kanagawa, 230-0045, Japan.
Sakata D; Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Izumi Y; Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Togo T; Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo, 113-0033, Japan.
Hattori Y; Department of Biochemistry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Kunimura K; Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Sakurai T; Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Honma T; Laboratory for Structure-Based Molecular Design, RIKEN Center for Biosystems Dynamics Research, Kanagawa, 230-0045, Japan.
Bamba T; Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Nakamura M; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Kanai M; Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo, 113-0033, Japan.
Suematsu M; Department of Biochemistry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Fukui Y; Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. Electronic address: .
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Źródło:
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Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2022 Jun 18; Vol. 609, pp. 183-188. Date of Electronic Publication: 2022 Apr 10.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: <2002- >: San Diego, CA : Elsevier
Original Publication: New York, Academic Press.
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MeSH Terms:
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CD8-Positive T-Lymphocytes*
Neoplasms*/drug therapy
Animals ; Cholesterol Esters ; GTPase-Activating Proteins ; Guanine Nucleotide Exchange Factors ; Mice ; Sulfotransferases ; Tumor Microenvironment
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Contributed Indexing:
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Keywords: Cancer immunotherapy; Cholesterol sulfate; DOCK2; Immune evasion; SULT2B1b; T cell exclusion
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Substance Nomenclature:
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0 (Cholesterol Esters)
0 (DOCK2 protein, mouse)
0 (GTPase-Activating Proteins)
0 (Guanine Nucleotide Exchange Factors)
EC 2.8.2.- (SULT2B1b protein, mouse)
EC 2.8.2.- (Sulfotransferases)
KU576NT9O9 (cholesteryl sulfate)
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Entry Date(s):
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Date Created: 20220422 Date Completed: 20220510 Latest Revision: 20220512
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Update Code:
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20240104
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DOI:
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10.1016/j.bbrc.2022.04.035
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PMID:
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35452959
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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 in vitro and suppressed CS production from cancer cells expressing SULT2B1b. In vivo 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.
Competing Interests: Declaration of competing interest Kyushu University, Keio University and The University of Tokyo have a patent application related to this work, in which T.U., Y.S., K.O., T. Togo, M.K., and Y.F. are listed as co-inventors.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
