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

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426975/
https://www.ncbi.nlm.nih.gov/pubmed/30894532
http://dx.doi.org/10.1038/s41467-019-09263-1
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author 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.
author_facet 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.
author_sort Cao, Yu
collection PubMed
description 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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spelling pubmed-64269752019-03-22 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. Nat Commun Article 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. Nature Publishing Group UK 2019-03-20 /pmc/articles/PMC6426975/ /pubmed/30894532 http://dx.doi.org/10.1038/s41467-019-09263-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
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
title ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression
title_full ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression
title_fullStr ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression
title_full_unstemmed ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression
title_short ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression
title_sort er stress-induced mediator c/ebp homologous protein thwarts effector t cell activity in tumors through t-bet repression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426975/
https://www.ncbi.nlm.nih.gov/pubmed/30894532
http://dx.doi.org/10.1038/s41467-019-09263-1
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