ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression

Yu Cao, Jimena Trillo-Tinoco, Rosa A. Sierra, Carmen Anadon, Wenjie Dai, Eslam Mohamed, Ling Cen, Tara L. Costich, Anthony Magliocco, Douglas Marchion, Richard Klar, Sven Michel, Frank Jaschinski, Richard R. Reich, Shikhar Mehrotra, Juan R. Cubillos-Ruiz, David H Munn, Jose R. Conejo-Garcia, Paulo C. Rodriguez

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Understanding the intrinsic mediators that render CD8 + T cells dysfunctional in the tumor microenvironment is a requirement to develop more effective cancer immunotherapies. Here, we report that C/EBP homologous protein (Chop), a downstream sensor of severe endoplasmic reticulum (ER) stress, is a major negative regulator of the effector function of tumor-reactive CD8 + T cells. Chop expression is increased in tumor-infiltrating CD8 + T cells, which correlates with poor clinical outcome in ovarian cancer patients. Deletion of Chop in T cells improves spontaneous antitumor CD8 + T cell immunity and boosts the efficacy of T cell-based immunotherapy. Mechanistically, Chop in CD8 + T cells is elevated primarily through the ER stress-associated kinase Perk and a subsequent induction of Atf4; and directly represses the expression of T-bet, a master regulator of effector T cell function. These findings demonstrate the primary role of Chop in tumor-induced CD8 + T cell dysfunction and the therapeutic potential of blocking Chop or ER stress to unleash T cell-mediated antitumor immunity.

Original languageEnglish (US)
Article number1280
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Transcription Factor CHOP
effectors
endoplasmic reticulum
Endoplasmic Reticulum Stress
Tumors
tumors
proteins
regulators
immunity
Immunotherapy
Immunity
Neoplasms
cancer
deletion
Tumor Microenvironment
acceleration (physics)
Ovarian Neoplasms
induction
Phosphotransferases
requirements

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Cao, Y., Trillo-Tinoco, J., Sierra, R. A., Anadon, C., Dai, W., Mohamed, E., ... Rodriguez, P. C. (2019). ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nature Communications, 10(1), [1280]. https://doi.org/10.1038/s41467-019-09263-1

ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. / Cao, Yu; Trillo-Tinoco, Jimena; Sierra, Rosa A.; Anadon, Carmen; Dai, Wenjie; Mohamed, Eslam; Cen, Ling; Costich, Tara L.; Magliocco, Anthony; Marchion, Douglas; Klar, Richard; Michel, Sven; Jaschinski, Frank; Reich, Richard R.; Mehrotra, Shikhar; Cubillos-Ruiz, Juan R.; Munn, David H; Conejo-Garcia, Jose R.; Rodriguez, Paulo C.

In: Nature Communications, Vol. 10, No. 1, 1280, 01.12.2019.

Research output: Contribution to journalArticle

Cao, Y, Trillo-Tinoco, J, Sierra, RA, Anadon, C, Dai, W, Mohamed, E, Cen, L, Costich, TL, Magliocco, A, Marchion, D, Klar, R, Michel, S, Jaschinski, F, Reich, RR, Mehrotra, S, Cubillos-Ruiz, JR, Munn, DH, Conejo-Garcia, JR & Rodriguez, PC 2019, 'ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression', Nature Communications, vol. 10, no. 1, 1280. https://doi.org/10.1038/s41467-019-09263-1
Cao, Yu ; Trillo-Tinoco, Jimena ; Sierra, Rosa A. ; Anadon, Carmen ; Dai, Wenjie ; Mohamed, Eslam ; Cen, Ling ; Costich, Tara L. ; Magliocco, Anthony ; Marchion, Douglas ; Klar, Richard ; Michel, Sven ; Jaschinski, Frank ; Reich, Richard R. ; Mehrotra, Shikhar ; Cubillos-Ruiz, Juan R. ; Munn, David H ; Conejo-Garcia, Jose R. ; Rodriguez, Paulo C. / ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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abstract = "Understanding the intrinsic mediators that render CD8 + T cells dysfunctional in the tumor microenvironment is a requirement to develop more effective cancer immunotherapies. Here, we report that C/EBP homologous protein (Chop), a downstream sensor of severe endoplasmic reticulum (ER) stress, is a major negative regulator of the effector function of tumor-reactive CD8 + T cells. Chop expression is increased in tumor-infiltrating CD8 + T cells, which correlates with poor clinical outcome in ovarian cancer patients. Deletion of Chop in T cells improves spontaneous antitumor CD8 + T cell immunity and boosts the efficacy of T cell-based immunotherapy. Mechanistically, Chop in CD8 + T cells is elevated primarily through the ER stress-associated kinase Perk and a subsequent induction of Atf4; and directly represses the expression of T-bet, a master regulator of effector T cell function. These findings demonstrate the primary role of Chop in tumor-induced CD8 + T cell dysfunction and the therapeutic potential of blocking Chop or ER stress to unleash T cell-mediated antitumor immunity.",
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AU - Dai, Wenjie

AU - Mohamed, Eslam

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AU - Rodriguez, Paulo C.

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