Cited by 848Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmune cells in cancer

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The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

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Scharping, Nicole E., Menk, Ashley V., Moreci, Rebecca S., Whetstone, Ryan D., Dadey, Rebekah E., Watkins, Simon C., Ferris, Robert L., Delgoffe, Greg M.·2016·Immunity

DOI 10.1016/j.immuni.2016.07.009PMC PMC5207350

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Abstract

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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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: Scharping, Nicole E.
Menk, Ashley V.
Dadey, Rebekah E.
Watkins, Simon C.
Ferris, Robert L.
Delgoffe, Greg M.
Venue: Immunity
Publisher: Elsevier BV
Published: 2016-08
Volume: 45
Issue: 2
Pages: 374-388
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2016.07.009
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 380 d)
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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The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

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