title: The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.
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.
authors: Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Nicole E
authors: NE
authors: Scharping
authors: Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA.
authors: Ashley V
authors: AV
authors: Menk
authors: Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA.
authors: Rebecca S
authors: RS
authors: Moreci
authors: Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Ryan D
authors: RD
authors: Whetstone
authors: Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Rebekah E
authors: RE
authors: Dadey
authors: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Simon C
authors: SC
authors: Watkins
authors: Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Robert L
authors: RL
authors: Ferris
authors: Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: gdelgoffe@pitt.edu.
authors: Greg M
authors: GM
authors: Delgoffe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D003110:Colonic Neoplasms / Q000276:immunology*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009374:Neoplasms, Experimental; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment
chemical_list: D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D051058:Oncogene Protein v-akt