Anlotinib combined with the PD-L1 blockade exerts the potent anti-tumor immunity in renal cancer treatment

Anlotinib have shown certain therapeutic effects of renal cell carcinoma (RCC), but drug resistance during treatment leads to the fact that the therapeutic effect is unsatisfactory. Herein, we investigated the tumor immune microenvironment about resistance mechanisms when application of Anlotinib and further improved its therapeutic effect. Our results showed that Anlotinib suppressed cell proliferation and promoted cell apoptosis in RCC cells. Meanwhile, the significantly up-regulated expression of PD-L1 was observed in Anlotinib-treated RCC cells by the concentration and time-dependent manner. Further study showed that Anlotinib-induced PD-L1 expression was regulated by autocrine IL-6 mediated JAK2/STAT3 signaling pathways. Interestingly, Anlotinib combined with PD-L1 blockade increased the infiltration of IFN-γ⁺CD8⁺ T cells and natural killer (NK) cells, also decreased the quantity of Treg cells and MDSCs in vivo. Likewise, the therapy above showed significantly synergistic therapeutic effect as demonstrated by reduced tumor volume and weight. These results indicated that the drug resistance might be attributed to the Anlotinib induced-PD-L1 mediated immunosuppression in renal cancer treatment. Anlotinib combined anti-PDL-1 treatment exerts the potential anti-tumor effect by promoting the induction and activation of immune killer cells. The therapeutic strategy of Anlotinib combined anti-PDL-1 could be a potential and promising approach for the therapy of renal cancer or other malignant tumors.