C/EBPβ enhances immunosuppression activity of myeloid-derived suppressor cells by a P300-mediated acetylation modification

Objective: Myeloid-derived suppressor cells (MDSCs) are a major immunosuppressive population in the tumor microenvironment,inhibiting anti-tumor immune response and exerting pro-tumorigenic effect. CCAAT/enhancer-binding protein beta (C/EBPβ), a key transcription factor indispensable for myelopoiesis, plays a fundamental role in regulating expansion and activation of MDSCs. Lysine acetylation can regulate functions of transcription factors. However, the role of C/EBPβ acetylation modification in MDSCs has not been reported.

Materials and methods: MDSCs derived from the spleens of tumor-bearing mice (TB-SP-MDSCs) were isolated by immunomagnetic beads. Bone marrow derived MDSCs were induced by IL-6 and GM-CSF. Western-blot was used to detect the expression of P300 and co-immunoprecipitation (CO-IP) was used to detect the C/EBPβ acetylation in MDSCs. Inhibitor C646 was used to specificly inhibit P300 activity.

Results: In this study, we found that C/EBPβ was acetylated by acetyltransferase P300 in MDSCs. A P300-mediated C/EBPβ acetylation enhanced C/EBPβ transactivation activity on Arginase 1 (Arg-1) gene promoter. Inhibition of P300 activity downregulated the inhibitory effects of MDSCs in vitro and attenuated pro-tumorigenic effects of MDSCs in vivo. Additionally, IL-6 from tumor microenvironment could upregulate the expression of P300 and enhance C/EBPβ acetylation in MDSCs.

Conclusion: In general, a P300-mediated C/EBPβ acetylation enhanced C/EBPβ transactivation activity on Arg-1 promoter, thus promoting immunosuppressive function of MDSCs. In view of the critical role of P300 in regulating MDSCs, P300 might be a potential target of anti-tumor immunotherapy.

Acetylation; C/EBPβ; Immunosuppression; Myeloid-derived suppressor cells; P300.