| First Author | Cao Y | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 1280 |
| PubMed ID | 30894532 | Mgi Jnum | J:273454 |
| Mgi Id | MGI:6286881 | Doi | 10.1038/s41467-019-09263-1 |
| Citation | Cao Y, et al. (2019) ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat Commun 10(1):1280 |
| abstractText | 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. |
