Cited by 576T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersMitochondrial Function and Pathology

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Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen

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Vardhana, Santosha A., Hwee, Madeline A., Berisa, Mirela, Wells, Daniel K., Yost, Kathryn E., King, Bryan, Smith, Melody, Herrera, Pamela S., Chang, Howard Y., Satpathy, Ansuman T., van den Brink, Marcel R. M., Cross, Justin R., Thompson, Craig B.·2020·Nature Immunology

DOI 10.1038/s41590-020-0725-2PMC PMC7442749

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Abstract

The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity. Thompson and colleagues show that repetitive antigenic stimulation within the tumor environment triggers mitochondrial dysfunction by inhibiting oxidative phosphorylation, which leads to T cell exhaustion.

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Authors: Vardhana, S. A., Hwee, M. A., Berisa, M., Wells, D. K., Yost, K. E., King, B., Smith, M., Herrera, P. S., Chang, H. Y., Satpathy, A. T., van den Brink, M. R. M., Cross, J. R., & Thompson, C. B.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Parker Institute for Cancer Immunotherapy (US)
Stanford Medicine (US)
Howard Hughes Medical Institute (US)
Corresponding author: Thompson, Craig B.
ORCID: Vardhana, Santosha A.
Berisa, Mirela
Wells, Daniel K.
Yost, Kathryn E.
King, Bryan
Smith, Melody
Chang, Howard Y.
Satpathy, Ansuman T.
Cross, Justin R.
Thompson, Craig B.
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2020-07-13
Volume: 21
Issue: 9
Pages: 1022-1033
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/s41590-020-0725-2
PMC: PMC7442749
OpenAlex: W3040911066
Semantic Scholar: 0e26544b84036d0da9a73a3a38337fc7b1573819
Cited by: 575
References: 67
Citations by year: 2026: 133 · 2025: 117 · 2024: 112 · 2023: 90 · 2022: 68 · 2021: 46 · 2020: 9
FWCI: 18.62
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health (1r01hl147584-01a1)
National Heart, Lung, and Blood Institute (R01‐HL147584)
National Cancer Institute (K08CA237731, P30CA008748)
National Institute of Allergy and Infectious Diseases (R25AI140472)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords: T cell exhaustion, mitochondrial oxidative phosphorylation, T cell self-renewal, chronic antigenic stimulation, T cell proliferation, mitochondrial oxidative stress, antioxidant treatment, redox homeostasis, tumor-infiltrating T cells, antitumor immunity
MeSH terms: Cell Self Renewal, Adenosine Diphosphate, Animals, Antigens, Neoplasm, Antioxidants, Energy Metabolism, Immune Tolerance, Lymphocyte Activation, Melanoma, Experimental, Mice, Inbred C57BL, Mitochondria, Neoplasms, Oxidative Phosphorylation, Lymphocytes, Tumor-Infiltrating, Clonal Anergy, CD8-Positive T-Lymphocytes, Cell Proliferation, Mice

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Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen

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