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

• Published in: Cancer gene therapy 2021-02, Vol.28 (1-2), p.89-97
• Main Authors: Yang, Yinli, Wang, Cong, Sun, Haiyan, Jiang, Zhansheng, Zhang, Yu, Pan, Zhanyu
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 13/51; 14/1; 631/67/1059/602; 631/67/580; 64/60; Animal models; Animals; Antitumor activity; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; CD4 antigen; CD8 antigen; Disease Models, Animal; Drug therapy; Enzyme inhibitors; Female; Gene Expression; Gene Therapy; Health aspects; Hepatocellular carcinoma; Hepatoma; Humans; Immunotherapy; Immunotherapy - methods; Interleukin 6; Killer cells; Killer Cells, Natural; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Lymphocytes T; Mice; Natural killer cells; Oncology, Experimental; PD-1 protein; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Pyridines - pharmacology; Pyridines - therapeutic use; Solid tumors; Tumor necrosis factor-α; Vascular endothelial growth factor; Vascular endothelial growth factor receptor 2; γ-Interferon
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-020-0186-7

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.