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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest: The authors declare no potential conflicts of interest.
Funding Information: This work was supported in part by JSPS KAKENHI (Grant No. JP22H03533, Grants-in-aid for Scientific Research (B)), The Mochida Memorial Foundation for Medical and Pharmaceutical Research, and a grant from The Drug Discovery Science Division, Open and Transdisciplinary Research Initiatives, Osaka University (M.T.). This study was partially supported by the Zhejiang Provincial Natural Science Foundation of China (Grant No. LQ23H160001) (Z.X.). This research was also partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) of AMED (Grant No. JP22ama121052 and JP22ama121054).