2. Academic Validation
  3. Blockade of myeloid-derived suppressor cell function by valproic acid enhanced anti-PD-L1 tumor immunotherapy

Blockade of myeloid-derived suppressor cell function by valproic acid enhanced anti-PD-L1 tumor immunotherapy

  • Biochem Biophys Res Commun. 2020 Feb 12;522(3):604-611. doi: 10.1016/j.bbrc.2019.11.155.
Adeleye O Adeshakin 1,  Dehong Yan 2,  Mengqi Zhang 3,  Lulu Wang 4,  Funmilayo O Adeshakin 1,  Wan Liu 2,  Xiaochun Wan 5
Affiliations

Affiliations

  • 1 Shenzhen Laboratory for Human Antibody Engineering, Center for Protein and Cell-based Drugs, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; University of Chinese Academy of Sciences, Beijing, 100864, China.
  • 2 Shenzhen Laboratory for Human Antibody Engineering, Center for Protein and Cell-based Drugs, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 3 Shenzhen Laboratory for Human Antibody Engineering, Center for Protein and Cell-based Drugs, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; School of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121000, China.
  • 4 Department of Pediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.
  • 5 Shenzhen Laboratory for Human Antibody Engineering, Center for Protein and Cell-based Drugs, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; University of Chinese Academy of Sciences, Beijing, 100864, China. Electronic address: xc.wan@siat.ac.cn.
PMID: 31785814 DOI: 10.1016/j.bbrc.2019.11.155
Abstract

Regardless of the remarkable clinical success of immune checkpoint blockade (ICB) against PD-1/PD-L1 pathway, this approach has encountered drawbacks in most patients due to the activation of tumor immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Histone deacetylase (HDAC) inhibitors combat ICB resistance by attenuating the immunosuppressive function of MDSCs and increasing PD-L1 expression on tumor cells. However, whether an HDAC Inhibitor - valproic acid (VPA) suppression of MDSCs function could enhance PD-L1 blockade-mediated tumor immunotherapy remains unknown. Here we report that VPA and anti-PD-L1 antibody combined treatment promoted the polarization of bone marrow-derived precursor cells into M-MDSCs. Interestingly, the combination treatment of VPA and anti-PD-L1 antibody activated IRF1/IRF8 transcriptional axis in MDSCs leading to blockade of their immunosuppressive function by downregulating the expression of IL-10, IL-6, and ARG1 while re-activating CD8+ T-cells for the production of TNFα to further enhance anti-tumor immunity. These observations provide further rationale for the combination therapy of VPA with anti-PD-L1 antibody in preclinical settings.

Keywords

Anti-PD-L1 tumor immunotherapy; IRF1/IRF8; Myeloid-derived suppressor cell; Valproic acid.

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