Journal Article

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

Mohamed, Eslam, Marchion, Douglas, Michel, Sven, Costich, Tara L., Trillo-Tinoco, Jimena, Jaschinski, Frank, Munn, David H., Conejo-Garcia, Jose R., Reich, Richard R., Cubillos-Ruiz, Juan R., Klar, Richard, Cao, Yu, Sierra, Rosa A., Anadon, Carmen, Magliocco, Anthony, Mehrotra, Shikhar, Dai, Wenjie, Rodriguez, Paulo C., Cen, Ling

2019

Overview

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.”

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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) / 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