title: Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism.
abstract: CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.
authors.affiliation: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shuokai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiangbo
authors.initials: X
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lunyi
authors.initials: L
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Protein Science, School of Life Sciences, Collaborative Innovation Center for Infectious Diseases, Tsinghua University, Beijing 100084, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Protein Science, School of Life Sciences, Collaborative Innovation Center for Infectious Diseases, Tsinghua University, Beijing 100084, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Chengsong
authors.initials: C
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Haven 03755, USA.
authors.forename: Catharine C Y
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Haven 03755, USA.
authors.forename: Ta-Yuan
authors.initials: TY
authors.lastname: Chang
authors.affiliation: Rheumatology and Immunology Department of ChangZheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Penghui
authors.initials: P
authors.lastname: Zhou
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, Hubei Province 430072, China.
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Song
authors.affiliation: MOE Key Laboratory of Protein Science, School of Life Sciences, Collaborative Innovation Center for Infectious Diseases, Tsinghua University, Beijing 100084, China.
authors.forename: Wanli
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors.forename: Shao-cong
authors.initials: SC
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Bo-liang
authors.initials: BL
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.
authors.forename: Chenqi
authors.initials: C
authors.lastname: Xu
mesh_terms: D000081:Acetamides; D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004951:Esterification / Q000187:drug effects; D005260:Female; D054992:Immunological Synapses / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000081:Acetamides; D000085:Acetates; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D013449:Sulfonamides; D013451:Sulfonic Acids; C423185:avasimibe; D002784:Cholesterol; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase