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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / physiology*
  • Gene Knockout Techniques
  • Humans
  • Immunologic Memory
  • Immunotherapy
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Mice
  • Mitochondria / metabolism*
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / metabolism
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / metabolism
  • Reactive Oxygen Species / metabolism
  • Sarcoma / pathology
  • Sarcoma / therapy
  • Signal Transduction
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Reactive Oxygen Species
  • Ero1l protein, mouse
  • Oxidoreductases
  • PERK kinase
  • eIF-2 Kinase