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Cited by 1,010Cancer Immunotherapy and BiomarkersCancer, Lipids, and MetabolismImmunotherapy and Immune Responses

Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism

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Yang, Wei, Bai, Yibing, Xiong, Ying, Zhang, Jin, Chen, Shuokai, Zheng, Xiaojun, Meng, Xiangbo, Li, Lunyi +14 more·2016·Nature
DOI 10.1038/nature17412PMC PMC4851431
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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.

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  • Plasma membrane cholesterol abundance is required for T-cell receptor clustering and signaling.

    “Cholesterol is required to support the rapid clonal expansion of T cells post-activation (39, 40); plasma membrane cholesterol abundance being required for T-cell receptor clustering and signaling (69).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [69]

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Research works printed but not linked: 33

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Authors
Yang, W., Bai, Y., Xiong, Y., Zhang, J., Chen, S., Zheng, X., Meng, X., Li, L., Wang, J., Xu, C., Yan, C., Wang, L., Chang, C. C. Y., Chang, T.-Y., Zhang, T., Zhou, P., Song, B.-L., Liu, W., Sun, S.-C., Liu, X., Li, B.-L., & Xu, C.
Affiliations
  • Chinese Academy of Sciences (CN)
  • Tsinghua University (CN)
  • Dartmouth College (US)
  • Sun Yat-sen University Cancer Center (CN)
  • Wuhan University (CN)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
  • Xu, Chenguang
  • Xu, Chenqi
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2016-03-16
Volume
531
Issue
7596
Pages
651-655
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature17412
PMC
PMC4851431
OpenAlex
W2299840252
Cited by
1,010
References
5
Citations by year
2026: 99 · 2025: 127 · 2024: 133 · 2023: 131 · 2022: 134 · 2021: 120 · 2020: 107 · 2019: 42 · 2018: 48 · 2017: 45 · 2016: 22
FWCI
28.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institute on Aging (R01AG037609)
  • National Heart, Lung, and Blood Institute (HL60306, R01HL060306)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
ACAT1, ACAT2, cholesterol esterification, CD8+ T cells, antitumor immunity, avasimibe, melanoma, immunological synapse, T cell receptor signaling, plasma membrane cholesterol, anti-PD-1 combination therapy, cancer immunotherapy, tumor microenvironment, T cell proliferation, tumour metastasis
MeSH terms
Acetamides, Acetates, Acetyl-CoA C-Acetyltransferase, Animals, Cell Membrane, Cholesterol, Esterification, Female, Immunotherapy, Male, Melanoma, Receptors, Antigen, T-Cell, Sulfonamides, Sulfonic Acids, Signal Transduction, CD8-Positive T-Lymphocytes, Atherosclerosis, Mice, Immunological Synapses, Programmed Cell Death 1 Receptor

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