Lenvatinib Enhances T Cell Immunity and the Efficacy of Adoptive Chimeric Antigen Receptor-Modified T Cells by Decreasing Myeloid-Derived Suppressor Cells in Cancer

Abstract

Background: Lenvatinib, a tyrosine kinase inhibitor, has been approved for the treatment of several cancers. However, its regulatory activity and related mechanisms on T cell antitumour immunity need to be further investigated. Methods: The antitumour activity of lenvatinib in immunocompetent and immunodeficient mice was compared to determine the role of T cell immunity. The antitumour activity of T cells was analysed by cytokine production and adoptive T cell therapy. The immunosuppressive effects of MDSCs on T cells were determined by detecting cytokine production in T cells after being cocultured with MDSCs. The adjuvant immunotherapy effect of lenvatinib was determined by combination therapy with CAR-T cells in a murine renal cancer model. Findings: The antitumour activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+ T cell depletion. Lenvatinib increased proliferation, tumour infiltration and antitumour activity of T cells. Importantly, adoptive transfer of lenvatinib-treated T cells showed a long-term antitumour response in vivo. Mechanistically, lenvatinib upregulated T cell-related chemokines (CXCL10 and CCL8) in tumours and decreased the frequency and immunosuppressive activity of MDSCs. Furthermore, lenvatinib enhanced the efficacy of CAR-T cells in a murine renal cancer model. Interpretation: Our study revealed novel antitumour mechanisms of lenvatinib by enhancing T cell-mediated antitumour immunity. These findings are of great significance for guiding the clinical use of lenvatinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies. Funding: National Science Foundation of China (81773253), Jiangsu Province Social Development Projects (SBE2018740637, BE2020641), Youth Technology Innovation Team of Xuzhou Medical University (TD202003), Jiangsu Provincial Key Medical Discipline (ZDXKA2016014). Declaration of Interest: None to declare. Ethical Approval: All animal procedures were approved and manipulated in strict accordance with the Institutional Ethical Care and Use Committee.