ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression

• Published in: Nature communications Vol. 10; no. 1; p. 1280
• Main Authors: Cao, Yu, Trillo-Tinoco, Jimena, Sierra, Rosa A., Anadon, Carmen, Dai, Wenjie, Mohamed, Eslam, Cen, Ling, Costich, Tara L., Magliocco, Anthony, Marchion, Douglas, Klar, Richard, Michel, Sven, Jaschinski, Frank, Reich, Richard R., Mehrotra, Shikhar, Cubillos-Ruiz, Juan R., Munn, David H., Conejo-Garcia, Jose R., Rodriguez, Paulo C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.03.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/105; 13/106; 13/109; 13/31; 13/89; 13/95; 14/1; 14/63; 631/67/580; 631/67/580/1884; 82/80; 96/21; Activating Transcription Factor 4 - antagonists & inhibitors; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - immunology; Adoptive Transfer; Animals; Cancer; Cancer immunotherapy; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - immunology; Carcinoma, Ovarian Epithelial - mortality; Carcinoma, Ovarian Epithelial - therapy; CCAAT/enhancer-binding protein; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Line, Tumor; Cell-mediated immunity; Clonal deletion; eIF-2 Kinase - antagonists & inhibitors; eIF-2 Kinase - genetics; eIF-2 Kinase - immunology; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Female; Gene Expression Regulation, Neoplastic - immunology; Homology; Humanities and Social Sciences; Humans; Immunity; Immunity, Cellular; Immunotherapy; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Mice; Mice, Knockout; multidisciplinary; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Ovarian Neoplasms - mortality; Ovarian Neoplasms - therapy; Proteins; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Stress; Survival Analysis; T-Box Domain Proteins - genetics; T-Box Domain Proteins - immunology; Transcription Factor CHOP - antagonists & inhibitors; Transcription Factor CHOP - genetics; Transcription Factor CHOP - immunology; Tumor microenvironment; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09263-1

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. T-cell function impairment is one of the major determinants of tumour immune evasion. Here, the authors show that the hostile conditions in the tumour microenvironment lead to C/EBP homologous-protein upregulation in T cells via ER stress, resulting in repression of T-bet and consequent inhibition of CD8 + T cell function.”