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

The DOI matches its Crossref record; 44 of the 45 references it cites were found in a registry or an index.

Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

Open access
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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Metadata

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
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
Licence
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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