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Abstract
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.