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

  • Immunity. 2016 Aug 16;45(2):374-88. doi: 10.1016/j.immuni.2016.07.009.
Nicole E Scharping  1 ,  Ashley V Menk  2 ,  Rebecca S Moreci  2 ,  Ryan D Whetstone  1 ,  Rebekah E Dadey  1 ,  Simon C Watkins  3 ,  Robert L Ferris  4 ,  Greg M Delgoffe  5
Affiliations
  • 1. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 2. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA.
  • 3. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 4. 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.
  • 5. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: [email protected].
PMID: 27496732 DOI: 10.1016/j.immuni.2016.07.009
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.