TY - JOUR
T1 - ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression
AU - Cao, Yu
AU - Trillo-Tinoco, Jimena
AU - Sierra, Rosa A.
AU - Anadon, Carmen
AU - Dai, Wenjie
AU - Mohamed, Eslam
AU - Cen, Ling
AU - Costich, Tara L.
AU - Magliocco, Anthony
AU - Marchion, Douglas
AU - Klar, Richard
AU - Michel, Sven
AU - Jaschinski, Frank
AU - Reich, Richard R.
AU - Mehrotra, Shikhar
AU - Cubillos-Ruiz, Juan R.
AU - Munn, David H
AU - Conejo-Garcia, Jose R.
AU - Rodriguez, Paulo C.
N1 - Funding Information:
The authors would like to thank J. Kroeger from the Flow Cytometry core; S. McCarthy and N. Lopez-Blanco from the CLIA Tissue Imaging core; S. Yoder from the Molecular Genomics Core; Y. Xu from the Cancer Informatics Core; and J. Johnson from the Analytic Microscopy Core. All used cores are partially funded through the NCI designated Moffitt Cancer Center Support Grant (CCSG) P30-CA076292. Support for the used shared resources was provided by the Cancer Center Support Grant (CCSG) CA076292 to Moffitt Cancer Center. This study was supported in part by the National Institutes of Health (NIH) grants: R01CA184185 to P.C.R.; R01CA103320 and R01CA211229 to D.H.M.; and R01CA157664, R01CA124515, R01CA178687, and U01CA232758 to J.C.-G. J.R.C.-R. was supported by the Ovarian Cancer Academy-Early-Career Investigator Award W81XWH-16-1-0438 of the Department of Defense (DOD).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-019-09263-1
DO - 10.1038/s41467-019-09263-1
M3 - Article
C2 - 30894532
AN - SCOPUS:85063340426
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1280
ER -
