Cited by 1,033Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

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Ma, Xingzhe, Bi, Enguang, Lu, Yong, Su, Pan, Huang, Chunjian, Liu, Lintao, Wang, Qiang, Yang, Maojie, Kalady, Matthew F., Qian, Jianfei, Zhang, Aijun, Gupte, Anisha A., Hamilton, Dale J., Zheng, Chengyun, Yi, Qing·2019·Cell Metabolism

DOI 10.1016/j.cmet.2019.04.002PMC PMC7061417

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Abstract

Tumor-infiltrating T cells often lose their effector function; however, the mechanisms are incompletely understood. We report that cholesterol in the tumor microenvironment induces CD8+ T cell expression of immune checkpoints and exhaustion. Tumor tissues enriched with cholesterol and cholesterol content in tumor-infiltrating CD8+ T cells were positively and progressively associated with upregulated T cell expression of PD-1, 2B4, TIM-3, and LAG-3. Adoptively transferred CD8+ T cells acquired cholesterol, expressed high levels of immune checkpoints, and became exhausted upon entering a tumor. Tumor culture supernatant or cholesterol induced immune checkpoint expression by increasing endoplasmic reticulum (ER) stress in CD8+ T cells. Consequently, the ER stress sensor XBP1 was activated and regulated PD-1 and 2B4 transcription. Inhibiting XBP1 or reducing cholesterol in CD8+ T cells effectively restored antitumor activity. This study reveals a mechanism underlying T cell exhaustion and suggests a new strategy for restoring T cell function by reducing cholesterol to enhance T cell-based immunotherapy.

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Authors: Ma, X., Bi, E., Lu, Y., Su, P., Huang, C., Liu, L., Wang, Q., Yang, M., Kalady, M. F., Qian, J., Zhang, A., Gupte, A. A., Hamilton, D. J., Zheng, C., & Yi, Q.
Affiliations: Houston Methodist (US)
Wake Forest University Health Sciences (US)
Cleveland Clinic (US)
Houston Methodist Research Institute (US)
Second Hospital of Shandong University (CN)
Corresponding author: Yi, Qing
ORCID: Ma, Xingzhe
Bi, Enguang
Lu, Yong
Liu, Lintao
Wang, Qiang
Kalady, Matthew F.
Qian, Jianfei
Zhang, Aijun
Gupte, Anisha A.
Hamilton, Dale J.
Zheng, Chengyun
Yi, Qing
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2019-07
Volume: 30
Issue: 1
Pages: 143-156.e5
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2019.04.002
PMC: PMC7061417
OpenAlex: W2941036215
Cited by: 1,033
References: 45
Citations by year: 2026: 176 · 2025: 204 · 2024: 187 · 2023: 169 · 2022: 136 · 2021: 100 · 2020: 47 · 2019: 12
FWCI: 31.24
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: cholesterol, CD8+ T cell exhaustion, tumor microenvironment, immune checkpoint, PD-1, 2B4, TIM-3, LAG-3, endoplasmic reticulum stress, XBP1, adoptive T cell therapy, antitumor immunity, cholesterol metabolism
MeSH terms: Animals, Cholesterol, Flow Cytometry, Humans, Immunotherapy, Melanoma, Experimental, Blotting, Western, CD8-Positive T-Lymphocytes, Immunoprecipitation, Mice, Tumor Microenvironment, Real-Time Polymerase Chain Reaction, Programmed Cell Death 1 Receptor

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Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

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