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

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. [Display omitted] •Chop regulates immune-suppressive activity and accumulation of MDSCs in tumors•Deletion of Chop in tumor stroma leads to effective antitumor T cell immunity•Reactive oxygen and nitrogen species in tumors trigger Chop in MDSCs through Atf4•Stromal cell Chop promotes MDSC activity through induction of C/EBPβ-IL-6 axis Very little is known about the interaction between tumor-linked cellular stress and antitumor immunity. Rodriguez and colleagues demonstrate an essential role for the stress-response sensor Chop in regulating the inhibitory function and accumulation of myeloid-derived suppressor cells in tumors.