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.
Highlights
The endoplasmic reticulum (ER) is an essential organelle that serves as the primary site for the production, assembly, and modification of proteins[12,13]
In agreement with our previous findings[19], we noticed an elevated expression of CHOP in tumor-infiltrating myeloid-derived suppressor cells (MDSC), which was more pronounced than that observed in CD8+ TILs (Supplementary Fig. 1e)
Our results reveal a new role of Chop as an intrinsic mediator of T cell dysfunction in tumors and suggest the therapeutic potential of inhibiting Chop or the unfolded protein responses (UPR) mediator Perk in CD8+ T cells as a platform to overcome tumor-induced T cell suppression and a strategy to boost the efficacy of T cell-based immunotherapies
Summary
The endoplasmic reticulum (ER) is an essential organelle that serves as the primary site for the production, assembly, and modification of proteins[12,13]. Despite the fact that the UPR signals regulate the activity of cancer cells and tumor-associated myeloid cells[24,25,26], the intrinsic effect of the UPR mediators in the dysfunction occurring in tumor-infiltrating T lymphocytes (TILs) remains unclear. Deletion or silencing of Chop potentiate cytotoxic T cell activity and overcome tumor-induced T cell dysfunction These findings show for the first time the therapeutic potential of blocking Chop in CD8+ T cells, or its upstream driver Perk, as a strategy to restore protective T cell immunity against cancer and a platform to enhance the effectiveness of T cell-based immunotherapies
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