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

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 (ERO1?). 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 ERO1? 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.

SUBMITTER: Hurst KE

PROVIDER: S-EPMC6397687 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8<sup>+</sup> T Cells.

Hurst Katie E KE Lawrence Kiley A KA Essman Matthew T MT Walton Zeke J ZJ Leddy Lee R LR Thaxton Jessica E JE

Cancer immunology research 20190118 3

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 ...[more]

PMID: 30659052

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Project description:Subcellular organelles communicate with each other to regulate function and coordinate responses to changing cellular conditions. The physical-functional coupling of the endoplasmic reticulum (ER) with mitochondria allows for the direct transfer of Ca2+ between organelles and is an important avenue for rapidly increasing mitochondrial metabolic activity. As such, increasing ER-mitochondrial coupling can boost the generation of ATP that is needed to restore homeostasis in the face of cellular stress. The mitochondrial unfolded protein response (mtUPR) is activated by the accumulation of unfolded proteins in mitochondria. Retrograde signaling from mitochondria to the nucleus promotes mtUPR transcriptional responses aimed at restoring protein homeostasis. It is currently unknown whether the changes in mitochondrial-ER coupling also play a role during mtUPR stress. We hypothesized that mitochondrial stress favors an expansion of functional contacts between mitochondria and ER, thereby increasing mitochondrial metabolism as part of a protective response. Hela cells were treated with doxycycline, an antibiotic that inhibits the translation of mitochondrial-encoded proteins to create protein disequilibrium. Treatment with doxycycline decreased the abundance of mitochondrial encoded proteins while increasing expression of CHOP, C/EBPβ, ClpP, and mtHsp60, markers of the mtUPR. There was no change in either mitophagic activity or cell viability. Furthermore, ER UPR was not activated, suggesting focused activation of the mtUPR. Within 2 h of doxycycline treatment, there was a significant increase in physical contacts between mitochondria and ER that was distributed throughout the cell, along with an increase in the kinetics of mitochondrial Ca2+ uptake. This was followed by the rise in the rate of oxygen consumption at 4 h, indicating a boost in mitochondrial metabolic activity. In conclusion, an early phase of the response to doxycycline-induced mitochondrial stress is an increase in mitochondrial-ER coupling that potentiates mitochondrial metabolic activity as a means to support subsequent steps in the mtUPR pathway and sustain cellular adaptation.

Dataset Information

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

Publications

Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8<sup>+</sup> T Cells.

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