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

被引:73
作者
Hurst, Katie E. [1 ]
Lawrence, Kiley A. [1 ]
Essman, Matthew T. [1 ,2 ]
Walton, Zeke J. [1 ,3 ]
Leddy, Lee R. [1 ,3 ]
Thaxton, Jessica E. [1 ,3 ,4 ]
机构
[1] Med Univ South Carolina, Sch Med, Coll Med, Dept Orthoped, Charleston, SC 29425 USA
[2] Med Univ South Carolina, Sch Med, Charleston, SC 29425 USA
[3] Med Univ South Carolina, Sch Med, Hollings Canc Ctr, Charleston, SC 29425 USA
[4] Med Univ South Carolina, Sch Med, Dept Microbiol & Immunol, Charleston, SC 29425 USA
关键词
PROTEIN-SYNTHESIS; RECEPTOR PD-1; DIFFERENTIATION; ANTITUMOR; EFFECTOR; ER; METABOLISM; ACTIVATION; INHIBITOR; CANCER;
D O I
10.1158/2326-6066.CIR-18-0182
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (ERO1a). To test this hypothesis, we created TCR transgenic mice with a T-cellspecific PERK gene deletion (OT1(+) Lckcre(+) PERKf/f, PERK KO). We found that PERK KO and T cells that were pharmacologically inhibited by PERK or ERO1a 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 antigenspecific 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.
引用
收藏
页码:476 / 486
页数:11
相关论文
共 48 条
  • [1] Translation is actively regulated during the differentiation of CD8+ effector T cells
    Araki, Koichi
    Morita, Masahiro
    Bederman, Annelise G.
    Konieczny, Bogumila T.
    Kissick, Haydn T.
    Sonenberg, Nahum
    Ahmed, Rafi
    [J]. NATURE IMMUNOLOGY, 2017, 18 (09) : 1046 - +
  • [2] Characterization of a Novel PERK Kinase Inhibitor with Antitumor and Antiangiogenic Activity
    Atkins, Charity
    Liu, Qi
    Minthorn, Elisabeth
    Zhang, Shu-Yun
    Figueroa, David J.
    Moss, Katherine
    Stanley, Thomas B.
    Sanders, Brent
    Goetz, Aaron
    Gaul, Nathan
    Choudhry, Anthony E.
    Alsaid, Hasan
    Jucker, Beat M.
    Axten, Jeffrey M.
    Kumar, Rakesh
    [J]. CANCER RESEARCH, 2013, 73 (06) : 1993 - 2002
  • [3] Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK)
    Axten, Jeffrey M.
    Medina, Jesus R.
    Feng, Yanhong
    Shu, Arthur
    Romeril, Stuart P.
    Grant, Seth W.
    Li, William Hoi Hong
    Heerding, Dirk A.
    Minthorn, Elisabeth
    Mencken, Thomas
    Atkins, Charity
    Liu, Qi
    Rabindran, Sridhar
    Kumar, Rakesh
    Hong, Xuan
    Goetz, Aaron
    Stanley, Thomas
    Taylor, J. David
    Sigethy, Scott D.
    Tomberlin, Ginger H.
    Hassell, Annie M.
    Kahler, Kirsten M.
    Shewchuk, Lisa M.
    Gampe, Robert T.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (16) : 7193 - 7207
  • [4] Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8+ T Cell Exhaustion
    Bengsch, Bertram
    Johnson, Andy L.
    Kurachi, Makoto
    Odorizzi, Pamela M.
    Pauken, Kristen E.
    Attanasio, John
    Stelekati, Erietta
    McLane, Laura M.
    Paley, Michael A.
    Delgoffe, Greg M.
    Wherry, E. John
    [J]. IMMUNITY, 2016, 45 (02) : 358 - 373
  • [5] A Small Molecule Inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with Selectively Reversible Thiol Reactivity
    Blais, Jaime D.
    Chin, King-Tung
    Zito, Ester
    Zhang, Yuhong
    Heldman, Nimrod
    Harding, Heather P.
    Fass, Deborah
    Thorpe, Colin
    Ron, David
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (27) : 20993 - 21003
  • [6] ROLE OF ATP AND DISULFIDE BONDS DURING PROTEIN FOLDING IN THE ENDOPLASMIC-RETICULUM
    BRAAKMAN, I
    HELENIUS, J
    HELENIUS, A
    [J]. NATURE, 1992, 356 (6366) : 260 - 262
  • [7] Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming
    Buck, Michael D.
    O'Sullivan, David
    Geltink, Ramon I. Klein
    Curtis, Jonathan D.
    Chang, Chih-Hao
    Sanin, David E.
    Qiu, Jing
    Kretz, Oliver
    Braas, Daniel
    van der Windt, Gerritje J. W.
    Chen, Qiongyu
    Huang, Stanley Ching-Cheng
    O'Neill, Christina M.
    Edelson, Brian T.
    Pearce, Edward J.
    Sesaki, Hiromi
    Huber, Tobias B.
    Rambold, Angelika S.
    Pearce, Erika L.
    [J]. CELL, 2016, 166 (01) : 63 - 76
  • [8] T cell metabolism drives immunity
    Buck, Michael D.
    O'Sullivan, David
    Pearce, Erika L.
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2015, 212 (09) : 1345 - 1360
  • [9] PERK in beta cell biology and insulin biogenesis
    Cavener, Douglas R.
    Gupta, Sounak
    McGrath, Barbara C.
    [J]. TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2010, 21 (12) : 714 - 721
  • [10] Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity
    Chamoto, Kenji
    Chowdhury, Partha S.
    Kumar, Alok
    Sonomura, Kazuhiro
    Matsuda, Fumihiko
    Fagarasan, Sidonia
    Honjo, Tasuku
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2017, 114 (05) : E761 - E770