Format

Send to

Choose Destination
Nat Commun. 2019 Mar 20;10(1):1280. doi: 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.

Author information

1
Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
2
Cancer Informatics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
3
Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
4
Secarna Pharmaceuticals GmbH & Co. KG, 82152, Planegg/Martinsried, Germany.
5
Biostatistics Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
6
Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA.
7
Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, 10065, USA.
8
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
9
Department of Pediatrics, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA.
10
Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA. Paulo.Rodriguez@Moffitt.org.

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.

PMID:
30894532
PMCID:
PMC6426975
DOI:
10.1038/s41467-019-09263-1
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center