HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived
Zhiqi Xie1,2, Jinjin Shao3, Zeren Shen4
1Wuyi First People's Hospital, Affiliated Hospital, School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
Abstract:
Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic 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. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC.
Insights
Histone deacetylase (HDAC) inhibitors targeting HDAC1-3 reduce immunosuppressive myeloid-derived suppressor cells (MDSCs) by decreasing CCR2 expression. This approach enhances natural killer cell activity and potentiates immunotherapy in a hepatocellular carcinoma model.
Area of Science:
- Immunology
- Cancer Biology
- Epigenetics
Background:
- Myeloid-derived suppressor cells (MDSCs) are key regulators of tumor immune evasion and therapeutic resistance.
- Histone deacetylases (HDACs) influence cellular processes, but their specific role in MDSC function is not well understood.
Purpose of the Study:
- To investigate the impact and mechanisms of HDAC inhibitors on MDSCs.
- To evaluate the therapeutic potential of HDAC inhibitors in hepatocellular carcinoma (HCC).
Main Methods:
- Utilized various HDAC inhibitors in vitro and in an orthotropic HCC murine model.
- Performed ATAC-seq and RNA-seq analyses to identify epigenetic targets.
- Investigated CCR2 protein degradation pathways.
Main Results:
- HDAC1-3 inhibitors reduced monocytic MDSC (M-MDSC) infiltration and immunosuppressive activity by downregulating CCR2.
- Treatment suppressed tumor growth, increased natural killer cell infiltration, and enhanced anti-PD-1 therapy efficacy.
- Identified 115 epigenetically upregulated genes and elucidated CCR2 degradation via NEDD4 E3 ligase.
Conclusions:
- HDAC1-3 inhibitors offer a novel mechanism to modulate MDSCs by targeting CCR2 degradation.
- This strategy holds promise for synergistic immunotherapy in HCC treatment.
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