Eradication of hepatocellular carcinoma by augmenting PD-L1 blockade efficacy with suppression of cell-cycle related kinase (CCRK)-induced myeloid-derived suppressor cells

Abstract

Abstract Myeloid-derived suppressor cells (MDSCs) constitute to tumor immunosuppression and immune checkpoint blockade therapy resistance. We have recently reported the cell-autonomous pro-tumorigenic functions of cell cycle-related kinase (CCRK) in hepatocellular carcinoma (HCC), but its role in tumor immune evasion remains unknown. Here we report that the hepatoma-intrinsic CCRK signaling renders T-cell dysfunction by induction of MDSCs. CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR−MDSC generation from human PBMCs through up-regulating interleukin-6 (IL-6). Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) in an enhancer of zeste homolog 2 (EZH2)-dependent manner and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. In corroboration with the CCRK-inducible transgenic mouse model, we demonstrated that hepatic CCRK induced IL-6 to specifically expand and recruit polymorphonuclear-MDSCs with potent T-cell-inhibitory function to the liver. In contrast, genome-deletion of tumoral Ccrk expression or nanoparticle-mediated hepatic IL-6 inhibition increased cytotoxic IFN-γ+TNF-α+CD8+T-cell infiltration and impaired tumorigenicity, which was rescued by restoring polymorphonuclear-MDSCs. More importantly, Ccrk deletion significantly enhanced the efficacy of anti-PD-L1 therapy to eradicate large hepatoma in an intrahepatic model. As we also showed that CCRK positively correlated with the intra-tumoral CD11b+CD33+HLA-DR−MDSCs and poor survival rates of HCC patients, our results establish an immunosuppressive function of the hepatoma-intrinsic CCRK signaling and highlight a therapeutic target whose inhibition might potentiate cancer immunotherapy.