HDAC1-3 inhibition reduces CCR2 expression and immunosuppressive function of myeloid-derived suppressor cells

Abstract Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, making them significant targets for cancer immunotherapy. Although epigenetic regulation by histone deacetylases (HDACs) regulates cell fate and function, the specific roles of HDACs in modulating MDSCs remain poorly understood. We aimed to examine the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. HDAC1-3 inhibitors were found to reduce the expression of CCR2, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotopic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. To elucidate the molecular mechanisms underlying the inhibition of MDSCs by HDAC1-3 inhibitors, ATAC-seq and RNA-seq analyses were performed. We identified 115 genes that were epigenetically upregulated by HDAC1-3 inhibitors, related to transcriptional regulation and ubiquitination. HDAC1-3 inhibitors further reduced CCR2 protein expression by enhancing ubiquitination-mediated degradation. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential combination strategy with immunotherapy for the clinical translation of HCC.