The stress sensor CHOP enhances the accumulation and inhibitory activity of MDSCs in tumors.
Major finding: The stress sensor CHOP enhances the accumulation and inhibitory activity of MDSCs in tumors.
Mechanism: Tumor-derived reactive oxygen and nitrogen species induce CHOP expression in MDSCs through ATF4.
Impact: Targeting CHOP may overcome tumor-induced tolerance and enhance cancer immunotherapy.
Myeloid-derived suppressor cells (MDSC) accumulate within tumors and inhibit antitumor immune responses. However, the effects of tumor-induced stress responses on MDSC function remain unclear. Thevenot and colleagues found that expression of the cellular stress sensor C/EBP-homologous protein (CHOP) was increased in tumor-infiltrating MDSCs compared with other immune cell types. Stromal deletion of CHOP or generation of CHOP-deficient bone marrow chimeras reduced tumor growth in mice, suggesting a role for CHOP in the promotion of tumor growth. CHOP-deficient MDSCs exhibited enhanced accumulation in tumors, increased proliferation, and decreased apoptosis compared with wild-type MDSCs. In addition, CHOP deletion diminished the capacity of tumor-infiltrating MDSCs to inhibit activated T-cell proliferation and IFNγ production and resulted in reduced levels of molecules essential for MDSC activity. Moreover, CHOP-deficient MDSCs failed to induce T-cell tolerance in vivo and induced antitumor immune responses. This antitumor effect was dependent in part on increased infiltration and activation of CD8+ T cells. Accordingly, CHOP deletion enhanced the efficacy of adoptive T-cell immunotherapy in tumor-bearing mice. Expression of CHOP in MDSCs was mediated by tumor-derived reactive oxygen and nitrogen species, which induced integrated stress responses and activating transcription factor 4 (ATF4)–driven induction of CHOP. Consistent with this finding, CHOP induction was reversed by antioxidant treatment, leading to a decrease in tumor growth. CHOP deletion decreased the activity of C/EBPβ, a critical regulator of MDSC function, resulting in reduced IL6 production and lower levels of phosphorylated STAT3, whereas IL6 expression was sufficient to rescue the immunosuppressive functions of CHOP-deficient MDSCs and restore tumor growth. Collectively, these observations demonstrate a primary role for CHOP in MDSC-induced immune suppression and suggest the potential for strategies targeting CHOP to overcome immune tolerance in cancer.
Thevenot PT, Sierra RA, Raber PL, Al-Khami AA, Trillo-Tinoco J, Zarreii P, et al. The stress-response sensor CHOP regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity 2014;41:389–401.
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