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Cancer Immunol Res. 2019 Mar;7(3):476-486. doi: 10.1158/2326-6066.CIR-18-0182. Epub 2019 Jan 18.

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

Author information

1
Department of Orthopedics, College of Medicine, Medical University of South Carolina Medical School, Charleston, South Carolina.
2
Medical University of South Carolina Medical School, Charleston, South Carolina.
3
Hollings Cancer Center, Medical University of South Carolina Medical School, Charleston, South Carolina.
4
Department of Orthopedics, College of Medicine, Medical University of South Carolina Medical School, Charleston, South Carolina. thaxton@musc.edu.
5
Department of Microbiology and Immunology, Medical University of South Carolina Medical School, Charleston, South Carolina.
#
Contributed equally

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+ PERK f/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.

PMID:
30659052
PMCID:
PMC6397687
[Available on 2020-03-01]
DOI:
10.1158/2326-6066.CIR-18-0182

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