Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation

Abstract

Summary: Myeloid-derived suppressor cells (MDSCs) are found in most cancer malignancies and support tumorigenesis by suppressing immunity and promoting tumor growth. Here we identify the bromodomain (BRD) of CBP/EP300 as a critical regulator of H3K27 acetylation (H3K27ac) in MDSCs across promoters and enhancers of pro-tumorigenic target genes. In preclinical tumor models, in vivo administration of a CBP/EP300-BRD inhibitor (CBP/EP300-BRDi) alters intratumoral MDSCs and attenuates established tumor growth in immunocompetent tumor-bearing mice, as well as in MDSC-dependent xenograft models. Inhibition of CBP/EP300-BRD redirects tumor-associated MDSCs from a suppressive to an inflammatory phenotype through downregulation of STAT pathway-related genes and inhibition of Arg1 and iNOS. Similarly, CBP/EP300-BRDi decreases differentiation and suppressive function of human MDSCs in vitro. Our findings uncover a role of CBP/EP300-BRD in intratumoral MDSCs that may be targeted therapeutically to boost anti-tumor immunity. : de Almeida Nagata et al. investigate the regulation of intratumoral myeloid-derived suppressor cells (MDSCs) by the CBP/EP300 bromodomain (BRD). By modulating H3K27 acetylation of STAT-associated genes, CBP/EP300-BRD controls MDSC function. Inhibition of the BRD reduces tumor growth in pre-clinical models, suggesting that CBP/EP300-BRD may be targeted to boost anti-tumor immunity. Keywords: CBP, EP300, H3K27ac, bromodomain, myeloid-derived suppressive cells, tumors