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 - 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 -