Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma

Lenvatinib has been expected as an immunomodulator based on its marked anti-angiogenic property in immunotherapy for solid cancers. However, the mechanism by which the tumor immune microenvironment is edited in human cancer tissues remains to be elucidated. Here, we analyzed the multi-omics of serial tumor and blood samples during lenvatinib monotherapy in 51 patients with advanced hepatocellular carcinoma. Lenvatinib yielded survival benefits regardless of baseline immune subtypes as determined by expression of the extracted RNAs. While immune signatures associated with T-cell functions and interferon responses were enriched in the early phase of treatment, signatures associated with immunoinhibitory cells were downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings were consistently supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. Our study also identified interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies.