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

Publication ,  Journal Article
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 ...
Published in: Nat Commun
March 20, 2019

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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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

March 20, 2019

Volume

10

Issue

1

Start / End Page

1280

Location

England

Related Subject Headings

  • eIF-2 Kinase
  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Transcription Factor CHOP
  • T-Box Domain Proteins
  • Survival Analysis
  • RNA, Small Interfering
  • Ovarian Neoplasms
  • Mice, Knockout
  • Mice
 

Citation

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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. Nat Commun, 10(1), 1280. https://doi.org/10.1038/s41467-019-09263-1
Cao, Yu, Jimena Trillo-Tinoco, Rosa A. Sierra, Carmen Anadon, Wenjie Dai, Eslam Mohamed, Ling Cen, et al. “ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression.Nat Commun 10, no. 1 (March 20, 2019): 1280. https://doi.org/10.1038/s41467-019-09263-1.
Cao Y, Trillo-Tinoco J, Sierra RA, Anadon C, Dai W, Mohamed E, et al. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat Commun. 2019 Mar 20;10(1):1280.
Cao, Yu, et al. “ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression.Nat Commun, vol. 10, no. 1, Mar. 2019, p. 1280. Pubmed, doi:10.1038/s41467-019-09263-1.
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. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat Commun. 2019 Mar 20;10(1):1280.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

March 20, 2019

Volume

10

Issue

1

Start / End Page

1280

Location

England

Related Subject Headings

  • eIF-2 Kinase
  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Transcription Factor CHOP
  • T-Box Domain Proteins
  • Survival Analysis
  • RNA, Small Interfering
  • Ovarian Neoplasms
  • Mice, Knockout
  • Mice