Lenvatinib enhances antitumor immunity by promoting the infiltration of <scp>TCF1</scp>⁺<scp>CD8</scp>⁺ T cells in <scp>HCC</scp> via blocking <scp>VEGFR2</scp>

Abstract

Abstract Lenvatinib is the favorable treatment for advanced hepatocellular carcinoma (HCC), and it is currently undergoing phase III clinical trials. However, the specific effects of lenvatinib on PD1 + CD8 + T cells in HCC microenvironment have not been systematically studied. Here, we established an orthotopic hepa1‐6 mouse model treated with lenvatinib to investigate CD8 + T cells’ role in the tumor and spleen. We found an 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 antitumor effect of lenvatinib and function of PD1 + CD8 + T cells. The effects of the mTOR pathway on PD1 + CD8 + T cells after lenvatinib treatment were mediated by VEGFR2 inhibition. Overall, our work provides insight into the mechanism of lenvatinib's antitumor efficacy through exhausted CD8 + T cells in HCC treatment.