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 and Paulo C. Rodriguez ()
Additional contact information
Yu Cao: H. Lee Moffitt Cancer Center & Research Institute
Jimena Trillo-Tinoco: H. Lee Moffitt Cancer Center & Research Institute
Rosa A. Sierra: H. Lee Moffitt Cancer Center & Research Institute
Carmen Anadon: H. Lee Moffitt Cancer Center & Research Institute
Wenjie Dai: H. Lee Moffitt Cancer Center & Research Institute
Eslam Mohamed: H. Lee Moffitt Cancer Center & Research Institute
Ling Cen: H. Lee Moffitt Cancer Center & Research Institute
Tara L. Costich: H. Lee Moffitt Cancer Center & Research Institute
Anthony Magliocco: H. Lee Moffitt Cancer Center & Research Institute
Douglas Marchion: H. Lee Moffitt Cancer Center & Research Institute
Richard Klar: Secarna Pharmaceuticals GmbH & Co. KG
Sven Michel: Secarna Pharmaceuticals GmbH & Co. KG
Frank Jaschinski: Secarna Pharmaceuticals GmbH & Co. KG
Richard R. Reich: H. Lee Moffitt Cancer Center & Research Institute
Shikhar Mehrotra: Medical University of South Carolina
Juan R. Cubillos-Ruiz: Weill Cornell Medicine
David H. Munn: Augusta University
Jose R. Conejo-Garcia: H. Lee Moffitt Cancer Center & Research Institute
Paulo C. Rodriguez: H. Lee Moffitt Cancer Center & Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-09263-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09263-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-09263-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().