The Stress-Response Sensor Chop Regulates the Function and Accumulation of Myeloid-Derived Suppressor Cells in Tumors

Abstract

Summary Adaptation of malignant cells to the hostile milieu present in tumors is an important determinant for their survival and growth. However, the interaction between tumor-linked stress and anti-tumor 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 anti-tumor 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 phospho-STAT3. IL-6 over-expression 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.

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

“…Tumor MDSCs from Chop KO mice exhibited greater survival than wild-type MDSCs and were shifted toward stimulation, rather than suppression, of T cell responses. Decreased IL-6 production by MDSCs was observed and exogenous IL-6 could "rescue" the function of Chop KO MDSCs (74). However, the importance of CHOP in the immunosuppressive phenotype of MDSCs requires further characterization, since there is a lack of consensus among different groups on its role in tumor progression (75).…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Since hepatocellular carcinoma is induced by chronic inflammation, CHOP may promote tumorigenesis by modulating the tumor microenvironment and macrophage recruitment to the tumor . Furthermore, Chop deficiency promotes the anti-tumor activity of tumor-infiltrating myeloid-derived suppressor cells (MDSC) by decreasing IL-6 and phospho-STAT3, delaying tumor progression (Thevenot et al 2014). Unfortunately, many in vivo studies of CHOP use whole-body knockout mice, so it is not possible to understand the mechanistic basis for a phenotype.…”

MDSCs in cancer: Conceiving new prognostic and therapeutic targets

“…lineage resulted in reduced tumor growth, decreased MDSC trafficking to the tumor, and complete loss of their suppressive activity, which inversely correlated with a higher number of IFNγ-producing CD8 + T cells homing to the tumor bed [92].…”

“…C/EBP homologous protein (CHOP) is a transcription factor induced by endoplasmic reticulum (ER) stress. TDFs, including ROS, can activate ER stress response pathway in MDSCs by inducing CHOP up-regulation, leading to activation of STAT3 and C/EBPβ and downstream IL-6 production, which is then utilized in an autocrine loop by the same MDSCs [92]. Selective Chop genetic ablation in the myeloid it also supports MDSC immunosuppressive function by activating NOX2 enzyme and inducing the expression of S100A8/A9 proteins that directly bind components of NADPH oxidase complex, which in turn promotes the production of ROS.…”