Epigenetic Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Jane L. Grogan Department of Cancer Immunology, Genentech, South San Francisco, CA, USA
Myeloid-derived suppressor cells (MDSC) are found in most cancer malignancies and support tumorigenesis by suppressing immunity and promoting tumor growth. Here we identify CBP as an epigenetic regulator of MDSC, and specifically that its bromodomain (BRD) is required to regulate MDSC development, accumulation, and function. Mechanistically, a small molecule inhibitor of the CBP-BRD diverted MDSC differentiation in vitro to a less suppressive phenotype. This effect was translated in vivo in xenograft and syngeneic tumor models dependent on MDSC, where CBP-BRD inhibition was sufficient to limit tumor growth. CBP-BRD inhibitor also reduced global acetylation marks at the 27th lysine residue of the histone H3 protein (H3K27Ac) near MDSC genes shown to have reduced expression by RNAseq, implying that chromatin modifications modulated by CBP-BRD can control MDSC transcriptional programs. The MDSC genes controlled by CBP-BRD defined a signature that correlated with survival outcome in patients with MDSC-rich tumors such as kidney carcinoma. Our findings uncover an unexpected role of CBP-BRD in MDSC that may be exploited therapeutically to boost anti-tumor immunity in patients unresponsive to current immunotherapies.
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