The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors

Immunity. 2014 Sep 18;41(3):389-401. doi: 10.1016/j.immuni.2014.08.015.


Adaptation of malignant cells to the hostile milieu present in tumors is an important determinant of their survival and growth. However, the interaction between tumor-linked stress and antitumor immunity remains poorly characterized. Here, we show the critical role of the cellular stress sensor C/EBP-homologous protein (Chop) in the accumulation and immune inhibitory activity of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). MDSCs lacking Chop had decreased immune-regulatory functions and showed the ability to prime T cell function and induce antitumor responses. Chop expression in MDSCs was induced by tumor-linked reactive oxygen and nitrogen species and regulated by the activating-transcription factor-4. Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-β, leading to a decreased production of interleukin-6 (IL-6) and low expression of phospho-STAT3. IL-6 overexpression restored immune-suppressive activity of Chop-deficient MDSCs. These findings suggest the role of Chop in tumor-induced tolerance and the therapeutic potential of targeting Chop in MDSCs for cancer immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Transplantation
  • CCAAT-Enhancer-Binding Protein-beta / immunology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Endothelial Cells / metabolism
  • Female
  • Interleukin-6 / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / immunology
  • Neoplasms
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / immunology
  • Reactive Nitrogen Species / immunology
  • Reactive Oxygen Species / immunology
  • STAT3 Transcription Factor / biosynthesis
  • T-Lymphocytes / immunology*
  • Transcription Factor CHOP / biosynthesis
  • Transcription Factor CHOP / genetics*
  • Tumor Escape / immunology*


  • Atf4 protein, mouse
  • CCAAT-Enhancer-Binding Protein-beta
  • Ddit3 protein, mouse
  • Interleukin-6
  • Reactive Nitrogen Species
  • Reactive Oxygen Species
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Activating Transcription Factor 4
  • Transcription Factor CHOP