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The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction
Open accessAbstract
Although tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1α resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment.
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“Exhausted T cells and tumor-infiltrating NK cells also exhibit dysregulated mitochondrial biogenesis, a mechanism that has created interest in using strategies to improve mitochondrial biogenesis to promote tumor immunity (Scharping et al., 2016; Zheng et al., 2019).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Scharping et al., 2016
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- Scarpulla, 2011, Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochimica et Biophysica Acta (BBA) -, Molecular Cell Research, 1813, 1269
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Metadata
- Authors
- Scharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R. E., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M.
- Affiliations
- University of Pittsburgh (US)
- UPMC Hillman Cancer Center (US)
- Corresponding author
- Delgoffe, Greg M.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 45
- Issue
- 2
- Pages
- 374-388
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5207350
- OpenAlex
- W4294138012
- Cited by
- 848
- References
- 44
- Citations by year
- 2026: 136 · 2025: 111 · 2024: 113 · 2023: 97 · 2022: 109 · 2021: 90 · 2020: 76 · 2019: 42 · 2018: 33 · 2017: 34 · 2016: 7
- FWCI
- 20.82
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-09-20)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od016236-01)
- National Cancer Institute (P50CA121973, P50CA097190, P30CA047904)
- 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 › Immune cells in cancer
- Keywords
- tumor microenvironment, PGC-1α, Akt signaling, T cell metabolism, oxidative metabolism, tumor-infiltrating T cells, T cell dysfunction, immunosuppression, metabolic reprogramming, cancer immunotherapy
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Colonic Neoplasms, Humans, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Neoplasms, Experimental, T-Lymphocytes, Signal Transduction, Lymphocytes, Tumor-Infiltrating, Oxidative Stress, Cell Line, Tumor, PPAR gamma, Oncogene Protein v-akt, Mice, Tumor Microenvironment, Cellular Reprogramming
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