Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09263-1
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Funding
- NCI designated Moffitt Cancer Center Support Grant (CCSG) [P30-CA076292]
- Cancer Center Support Grant (CCSG) [CA076292]
- National Institutes of Health (NIH) [R01CA184185, R01CA103320, R01CA211229, R01CA157664, R01CA124515, R01CA178687, U01CA232758]
- Ovarian Cancer Academy-Early-Career Investigator Award of the Department of Defense (DOD) [W81XWH-16-1-0438]
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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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