1. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism
- Author
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Bai Yibing, Li-Juan Wang, Chengsong Yan, Catharine C.Y. Chang, S.H. Chen, Ying Xiong, Bao-Liang Song, Chenqi Xu, Xiaolong Liu, Jing Wang, Ti Zhang, Wanli Liu, Chenguang Xu, Xiangbo Meng, Wei Yang, L. Li, Shao Cong Sun, Jin Zhang, Ta-Yuan Chang, Bo-Liang Li, Xiaojun Zheng, and Penghui Zhou
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Immunological Synapses ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Receptors, Antigen, T-Cell ,Biology ,Acetates ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Models, Biological ,Article ,Immunological synapse ,03 medical and health sciences ,Interleukin 21 ,Mice ,Antigen ,Cancer immunotherapy ,Internal medicine ,Acetamides ,medicine ,Cytotoxic T cell ,Homeostasis ,Animals ,Acetyl-CoA C-Acetyltransferase ,Melanoma ,Sulfonamides ,Multidisciplinary ,Esterification ,Cell Membrane ,Immunotherapy ,Atherosclerosis ,030104 developmental biology ,Endocrinology ,Cholesterol ,Cancer research ,Female ,Receptor clustering ,Sulfonic Acids ,CD8 ,Signal Transduction - 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.
- Published
- 2015