Apatinib prevents natural killer cell dysfunction to enhance the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma

Apatinib, a selective vascular endothelial growth factor receptor 2-tyrosine kinase inhibitor, has demonstrated activity against a wide range of solid tumors, including advanced hepatocellular carcinoma (HCC). Preclinical and preliminary clinical results have confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) blockade. However, the immunologic mechanism of this combination therapy remains unclear. Here, using a syngeneic HCC mouse model, we demonstrated that treatment with apatinib resulted in attenuation of tumor growth and increased tumor vessel normalization. Moreover, our results indicated that natural killer cells, but not CD4+ or CD8+ T cells mediated the therapeutic efficacy of apatinib in HCC mouse models. As expected, the combined administration of apatinib and anti-PD-1 antibody into tumor-bearing mice generated potent immune responses resulting in a remarkable reduction of tumor growth. Furthermore, increased interferon-γ and decreased tumor necrosis factor-α and interleukin-6 levels were observed, suggesting the potential benefits of combination therapy with PD-1 blockade and apatinib in HCC.