Low-dose apatinib and CPT synergistically optimize the tumor microenvironment and enhance the antitumor effects of PD-1 inhibitors in hepatocellular carcinoma

Abstract

Abstract Background Apatinib is a selective vascular endothelial growth factor receptor 2-tyrosine kinase inhibitor (TKI) that has been shown to apply to a variety of solid tumors, including advanced hepatocellular carcinoma(HCC). Clinical outcome prove that the combination of apatinib and anti programmed death 1 (PD-1) inhibitors has a cooperate with anti-tumor effect. In this study, we investigated the synergistic enhancement of the antitumor effect of PD-1 inhibitor in HCC by camptothecin (CPT) and low-dose apatinib. Methods The effect of low-dose apatinib in combination with CPT on the antitumor effects of PD-1 inhibitor was evaluated in making use of the H22 mouse model (n = 32), which was divided into four treatment groups. Immunohistochemical staining and western blotting were used to detect nuclear factor erythroid 2-related factor 2 (Nrf2) as well as sequestosome 1 (p62), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), PD-1, and programmed cell death ligand 1 (PD-L1). Results The results showed that the average size of the tumor of the combination group was significantly less than that of the apatinib + PD-1 inhibitor group. The expression levels of Nrf2, p62, VEGFA,VEGFR2, PD-1, and PD-L1 in the apatinib + PD-1 inhibitor group were lower than those in the control group (P < 0.05). The expression levels of these genes were significantly lower in the combination group (P < 0.05). Conclusion There was no obvious difference in body weight and liver and kidney functions between the four groups of mice. In conclusion, CPT synergistically enhanced the antitumor effect of PD-1 inhibitor in HCC with low-dose apatinib.