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Research Article

Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8+ T Cells

Katie E. Hurst, Kiley A. Lawrence, Matthew T. Essman, Zeke J. Walton, Lee R. Leddy and Jessica E. Thaxton
Katie E. Hurst
Department of Orthopedics, College of Medicine, Medical University of South Carolina Medical School, Charleston, South Carolina.
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Kiley A. Lawrence
Department of Orthopedics, College of Medicine, Medical University of South Carolina Medical School, Charleston, South Carolina.
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Matthew T. Essman
Department of Orthopedics, College of Medicine, Medical University of South Carolina Medical School, Charleston, South Carolina.Medical University of South Carolina Medical School, Charleston, South Carolina.
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Zeke J. Walton
Department of Orthopedics, College of Medicine, Medical University of South Carolina Medical School, Charleston, South Carolina.Hollings Cancer Center, Medical University of South Carolina Medical School, Charleston, South Carolina.
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Lee R. Leddy
Department of Orthopedics, College of Medicine, Medical University of South Carolina Medical School, Charleston, South Carolina.Hollings Cancer Center, Medical University of South Carolina Medical School, Charleston, South Carolina.
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Jessica E. Thaxton
Department of Orthopedics, College of Medicine, Medical University of South Carolina Medical School, Charleston, South Carolina.Hollings Cancer Center, Medical University of South Carolina Medical School, Charleston, South Carolina.Department of Microbiology and Immunology, Medical University of South Carolina Medical School, Charleston, South Carolina.
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  • For correspondence: thaxton@musc.edu
DOI: 10.1158/2326-6066.CIR-18-0182
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Abstract

Tumor antigen–specific T cells rapidly lose energy and effector function in tumors. The cellular mechanisms by which energy loss and inhibition of effector function occur in tumor-infiltrating lymphocytes (TILs) are ill-defined, and methods to identify tumor antigen–specific TILs that experience such stress are unknown. Processes upstream of the mitochondria guide cell-intrinsic energy depletion. We hypothesized that a mechanism of T-cell–intrinsic energy consumption was the process of oxidative protein folding and disulfide bond formation that takes place in the endoplasmic reticulum (ER) guided by protein kinase R-like endoplasmic reticulum kinase (PERK) and downstream PERK axis target ER oxidoreductase 1 (ERO1α). To test this hypothesis, we created TCR transgenic mice with a T-cell–specific PERK gene deletion (OT1+Lckcre+PERKf/f, PERK KO). We found that PERK KO and T cells that were pharmacologically inhibited by PERK or ERO1α maintained reserve energy and exhibited a protein profile consistent with reduced oxidative stress. These T-cell groups displayed superior tumor control compared with T effectors. We identified a biomarker of ER-induced mitochondrial exhaustion in T cells as mitochondrial reactive oxygen species (mtROS), and found that PD-1+ tumor antigen–specific CD8+ TILs express mtROS. In vivo treatment with a PERK inhibitor abrogated mtROS in PD-1+ CD8+ TILs and bolstered CD8+ TIL viability. Combination therapy enabled 100% survival and 71% tumor clearance in a sarcoma mouse model. Our data identify the ER as a regulator of T-cell energetics and indicate that ER elements are effective targets to improve cancer immunotherapy.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received March 28, 2018.
  • Revision received September 23, 2018.
  • Accepted December 12, 2018.
  • Published first January 18, 2019.
  • ©2019 American Association for Cancer Research.

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Published OnlineFirst February 15, 2019
doi: 10.1158/2326-6066.CIR-18-0182

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Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8+ T Cells
Katie E. Hurst, Kiley A. Lawrence, Matthew T. Essman, Zeke J. Walton, Lee R. Leddy and Jessica E. Thaxton
Cancer Immunol Res February 15 2019 DOI: 10.1158/2326-6066.CIR-18-0182

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Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8+ T Cells
Katie E. Hurst, Kiley A. Lawrence, Matthew T. Essman, Zeke J. Walton, Lee R. Leddy and Jessica E. Thaxton
Cancer Immunol Res February 15 2019 DOI: 10.1158/2326-6066.CIR-18-0182
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Cancer Immunology Research
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