Lenvatinib enhances antitumor immunity by promoting the infiltration of TCF1 + CD8 + T cells in HCC via blocking VEGFR2.

Lenvatinib is the favorable treatment for advanced hepatocellular carcinoma (HCC). And is currently conducted in phase III clinical trials. However, the specific effects of Lenvatinib on PD1 + CD8 + T cells in HCC microenvironment has not been systematically studied. Here, we established orthotopic hepa1-6 mouse model treated with Lenvatinib to investigate CD8 + T cells role in the tumor and spleen. We found increasing proportion of TCF-1 + in PD1 + CD8 + T cells and proliferation of PD1 + CD8 + T cells after Lenvatinib treatment. Meanwhile, Lenvatinib treatment upregulated the expression of granzyme B on PD1 + CD8 + T cells both in vitro and in vivo. Lenvatinib activated the endogenous mTOR pathway of exhausted CD8 + T cells and mTOR pathway blockade eliminated the Lenvatinib anti-tumor effect and function of PD1 + CD8 + T cells. The effects of the mTOR pathway of PD1 + CD8 + T cells after Lenvatinib treatment mediated by VEGFR2 inhibition. Overall, our work provides insight into the mechanism of Lenvatinib antitumor efficacy through exhausted CD8 + T cells in HCC treatment.