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The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors #MMPMID25238096
Thevenot PT; Sierra RA; Raber PL; Al-Khami AA; Trillo-Tinoco J; Zarreii P; Ochoa AC; Cui Y; Del Valle L; Rodriguez PC
Immunity 2014[Sep]; 41 (3): 389-401 PMID25238096show ga
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-beta, 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.
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Immunity 2014 ; 41 (3): 389-401
