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

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.