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

Nat Commun. 2019 Mar 20;10(1):1280. doi: 10.1038/s41467-019-09263-1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / antagonists & inhibitors
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / immunology
  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinoma, Ovarian Epithelial / genetics*
  • Carcinoma, Ovarian Epithelial / immunology
  • Carcinoma, Ovarian Epithelial / mortality
  • Carcinoma, Ovarian Epithelial / therapy
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / immunology*
  • Humans
  • Immunity, Cellular
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice
  • Mice, Knockout
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / therapy
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • 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 / genetics
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / immunology

Substances

  • ATF4 protein, human
  • DDIT3 protein, human
  • RNA, Small Interfering
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • EIF2AK3 protein, human
  • eIF-2 Kinase