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

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

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

Open access

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

Open this paper in CoChat — free account Open PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1016/j.immuni.2016.07.009

Cites

44 of 44 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652
Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
Chang, C.-H., Qiu, J., O’Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D., Chen, Q., Gindin, M., Gubin, M. M., van der Windt, G. J. W., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.016 · Cited by 3,331
Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice
Kim, J. M., Rasmussen, J. P., & Rudensky, A. Y. (2006) · Nature Immunology · doi:10.1038/ni1428 · Cited by 1,827
Mitochondria as sensors and regulators of calcium signalling
Rizzuto, R., De Stefani, D., Raffaello, A., & Mammucari, C. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3412 · Cited by 1,781
Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape
Woo, S.-R., Turnis, M. E., Goldberg, M. V., Bankoti, J., Selby, M., Nirschl, C. J., Bettini, M. L., Gravano, D. M., Vogel, P., Liu, C. L., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-1620 · Cited by 1,647
Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development
van der Windt, G. J. W., Everts, B., Chang, C.-H., Curtis, J. D., Freitas, T. C., Amiel, E., Pearce, E. J., & Pearce, E. L. (2012) · Immunity · doi:10.1016/j.immuni.2011.12.007 · Cited by 1,540
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Ho, P.-C., Bihuniak, J. D., Macintyre, A. N., Staron, M., Liu, X., Amezquita, R., Tsui, Y.-C., Cui, G., Micevic, G., Perales, J. C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.012 · Cited by 1,462
PGC-1 coactivators: inducible regulators of energy metabolism in health and disease
Finck, B. N. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27794 · Cited by 1,461
Fueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363
Combination cancer immunotherapy and new immunomodulatory targets
Mahoney, K. M., Rennert, P. D., & Freeman, G. J. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4591 · Cited by 1,294
Regulation of pgc-1α, a nodal regulator of mitochondrial biogenesis
Fernandez-Marcos, P. J., & Auwerx, J. (2011) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.001917 · Cited by 1,237
Overcoming T cell exhaustion in infection and cancer
Pauken, K. E., & Wherry, E. J. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.008 · Cited by 1,220
T-cell exhaustion in the tumor microenvironment
Jiang, Y., Li, Y., & Zhu, B. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.162 · Cited by 1,197
Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders
Kauppinen, A., Suuronen, T., Ojala, J. O., Kaarniranta, K., & Salminen, A. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.06.007 · Cited by 1,016
T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment
Crespo, J., Sun, H., Welling, T. H., Tian, Z., & Zou, W. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.12.003 · Cited by 752
Tolerance and exhaustion: defining mechanisms of T cell dysfunction
Schietinger, A., & Greenberg, P. D. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.10.001 · Cited by 704
Adaptive Immune Resistance: How Cancer Protects from Immune Attack
Ribas, A. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0563 · Cited by 641
CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability
van der Windt, G. J. W., O’Sullivan, D., Everts, B., Huang, S. C.-C., Buck, M. D., Curtis, J. D., Chang, C.-H., Smith, A. M., Ai, T., Faubert, B., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221740110 · Cited by 523
Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells
Odorizzi, P. M., Pauken, K. E., Paley, M., Sharpe, A. H., & Wherry, E. J. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20142237 · Cited by 480
mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation
Pollizzi, K. N., Patel, C. H., Sun, I., Oh, M. H., Waickman, A. T., Wen, J., Delgoffe, G. M., & Powell, J. D. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77746 · Cited by 417
Self-citation
Cytometric assessment of mitochondria using fluorescent probes
Cottet‐Rousselle, C., Ronot, X., Leverve, X. M., & Mayol, J. (2011) · Cytometry Part A · doi:10.1002/cyto.a.21061 · Cited by 416
Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction
Zhao, E., Maj, T., Kryczek, I., Li, W., Wu, K., Zhao, L., Wei, S., Crespo, J., Wan, S., Vatan, L., et al. (2016) · Nature Immunology · doi:10.1038/ni.3313 · Cited by 405
Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy
Sukumar, M., Liu, J., Mehta, G. U., Patel, S. J., Roychoudhuri, R., Crompton, J. G., Klebanoff, C. A., Ji, Y., Li, P., Yu, Z., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.11.002 · Cited by 400
The Transcription Factor FoxO1 Sustains Expression of the Inhibitory Receptor PD-1 and Survival of Antiviral CD8+ T Cells during Chronic Infection
Staron, M. M., Gray, S. M., Marshall, H. D., Parish, I. A., Chen, J. H., Perry, C. J., Cui, G., Li, M. O., & Kaech, S. M. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.013 · Cited by 398
Direct Coupling of Transcription and mRNA Processing through the Thermogenic Coactivator PGC-1
Monsalve, M., Wu, Z., Adelmant, G., Puigserver, P., Fan, M., & Spiegelman, B. M. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00031-9 · Cited by 395
Akt Inhibition Enhances Expansion of Potent Tumor-Specific Lymphocytes with Memory Cell Characteristics
Crompton, J. G., Sukumar, M., Roychoudhuri, R., Clever, D. C., Gros, A., Eil, R. L., Tran, E., Hanada, K., Yu, Z., Palmer, D. C., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-2277 · Cited by 354
T cell metabolic fitness in antitumor immunity
Siska, P. J., & Rathmell, J. C. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.007 · Cited by 317
Changes in the carbohydrate metabolism of mitogenicellay stimulated human peripheral lymphocytes I. Stimulation by phytohaemagglutinin
Roos, D., & Loos, J. A. (1970) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(70)90182-0 · Cited by 296
Protein Kinase B Controls Transcriptional Programs that Direct Cytotoxic T Cell Fate but Is Dispensable for T Cell Metabolism
Macintyre, A. N., Finlay, D. K., Preston, G., Sinclair, L. V., Waugh, C. M., Tamas, P., Feijóo, C. G., Okkenhaug, K., & Cantrell, D. A. (2011) · Immunity · doi:10.1016/j.immuni.2011.01.012 · Cited by 278
Inhibitory Receptor Expression Depends More Dominantly on Differentiation and Activation than “Exhaustion” of Human CD8 T Cells
Legat, A., Speiser, D. E., Pircher, H., Zehn, D., & Marraco, S. A. F. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00455 · Cited by 248
Mutual Dependence of Foxo3a and PGC-1α in the Induction of Oxidative Stress Genes
Olmos, Y., Valle, I., Borniquel, S., Tiérrez, A., Soria, E., Lamas, S., & Monsalve, M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m807397200 · Cited by 229
Targeting regulatory T cells in tumors
Liu, C., Workman, C. J., & Vignali, D. A. A. (2016) · The FEBS Journal · doi:10.1111/febs.13656 · Cited by 228
Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy
La-Beck, N. M., Jean, G. W., Huynh, C., Alzghari, S. K., & Lowe, D. B. (2015) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1643 · Cited by 220
Perturbations in Mitochondrial Dynamics Induced by Human Mutant PINK1 Can Be Rescued by the Mitochondrial Division Inhibitor mdivi-1
Cui, M., Tang, X., Christian, W. V., Yoon, Y., & Tieu, K. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.066662 · Cited by 210
The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells
Álvarez-Guardia, D., Palomer, X., Coll, T., Davidson, M. M., Chan, T. O., Feldman, A. M., Laguna, J. C., & Vázquez‐Carrera, M. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq080 · Cited by 190
TNF-α reduces PGC-1α expression through NF-κB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model
Palomer, X., Álvarez-Guardia, D., Rodríguez‐Calvo, R., Coll, T., Laguna, J. C., Davidson, M. M., Chan, T. O., Feldman, A. M., & Vázquez‐Carrera, M. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn327 · Cited by 178
Tumor necrosis factor and interleukin 1 decrease RXRα, PPARα, PPARγ, LXRα, and the coactivators SRC-1, PGC-1α, and PGC-1β in liver cells
Kim, M. S., Sweeney, T. R., Shigenaga, J. K., Chui, L. G., Moser, A., Grunfeld, C., & Feingold, K. R. (2007) · Metabolism · doi:10.1016/j.metabol.2006.10.007 · Cited by 168
Flow Cytometry-Based Assessment of Mitophagy Using MitoTracker
Xiao, B., Deng, X., Zhou, W., & Tan, E.-K. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00076 · Cited by 129
Feeding an army: The metabolism of T cells in activation, anergy, and exhaustion
Delgoffe, G. M., & Powell, J. D. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.07.026 · Cited by 86
Self-citation
Targeting mitochondria as a therapeutic target in cancer
Wenner, C. E. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22788 · Cited by 82
Inactivation of Foxo3a and Subsequent Downregulation of PGC-1α Mediate Nitric Oxide-Induced Endothelial Cell Migration
Borniquel, S., García-Quintáns, N., Valle, I., Olmos, Y., Wild, B., Martínez‐Granero, F., Soria, E., Lamas, S., & Monsalve, M. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00175-10 · Cited by 76
Caveolae-Dependent and -Independent Uptake of Albumin in Cultured Rodent Pulmonary Endothelial Cells
Li, H., Li, J., Wasserloos, K., Wallace, C. T., Sullivan, M., Bauer, P. M., Stolz, D. B., Lee, J. S., Watkins, S. C., Croix, C. M. S., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081903 · Cited by 65
Self-citation
Transcriptional Control of Energy Homeostasis through the PGC1 Coactivators
Spiegelman, B. M. (2007) · Novartis Foundation symposium · doi:10.1002/9780470985571.ch2 · Cited by 55
Interferon-beta affects mitochondrial activity in CD4 + lymphocytes: Implications for mechanism of action in multiple sclerosis
Haghikia, A., Faissner, S., Pappas, D. J., Puła, B., Akkad, D. A., Arning, L., Ruhrmann, S., Duscha, A., Gold, R., Baranzini, S. E., et al. (2014) · Multiple Sclerosis Journal · doi:10.1177/1352458514561909 · Cited by 16

Flagged first, then by citations

Research works printed but not linked: 1

Scarpulla, 2011, Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochimica et Biophysica Acta (BBA) -, Molecular Cell Research, 1813, 1269

Sorted by citations

CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055318 · Cited by 2,054
The diverse functions of the PD1 inhibitory pathway
Sharpe, A. H., & Pauken, K. E. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.108 · Cited by 2,054
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade
Morad, G., Helmink, B. A., Sharma, P., & Wargo, J. A. (2021) · Cell · doi:10.1016/j.cell.2021.09.020 · Cited by 1,648
Metabolic support of tumour-infiltrating regulatory T cells by lactic acid
Watson, M. J., Vignali, P., Mullett, S. J., Overacre-Delgoffe, A. E., Peralta, R. M., Grebinoski, S., Menk, A. V., Rittenhouse, N., DePeaux, K., Whetstone, R. D., et al. (2021) · Nature · doi:10.1038/s41586-020-03045-2 · Cited by 1,319
Self-citation
Metabolic Instruction of Immunity
Buck, M. D., Sowell, R., Kaech, S. M., & Pearce, E. L. (2017) · Cell · doi:10.1016/j.cell.2017.04.004 · Cited by 1,270

See all 848

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks