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Immunity. 2016 Aug 16;45(2):374-88. doi: 10.1016/j.immuni.2016.07.009. Epub 2016 Aug 2.

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

Author information

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: gdelgoffe@pitt.edu.

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.

PMID:
27496732
PMCID:
PMC5207350
DOI:
10.1016/j.immuni.2016.07.009
[Indexed for MEDLINE]
Free PMC Article

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