Immunomodulatory effects of lenvatinib in patients with advanced thyroid cancer

Introduction
Tyrosine kinase inhibitors, including lenvatinib approved for advanced non-medullary thyroid cancer (TC), affect the immune system. As tumor-related inflammation contributes to TC pathogenesis, this study assesses the immunomodulatory effects of lenvatinib, focusing on myeloid cells.

Methods
Peripheral blood was collected from 16 lenvatinib-treated and 15 untreated TC patients (cross-sectional cohort), and from eight patients before and after > 1 month of lenvatinib (longitudinal cohort). Immune profiling included cell subset counts, proteomic analyses, and ex vivo cytokine assays in peripheral blood mononuclear cells (PBMCs) and monocytes. Monocytes from healthy donors were used to evaluate metabolic activity, reactive oxygen species (ROS) production, and phagocytosis. Tumor-intrinsic effects of lenvatinib were studied by proteomics and immunophenotyping of the TPC-1 cell line.

Results
Lenvatinib increased lymphocytes and reduced neutrophils. In both cohorts, lenvatinib modulated the inflammatory proteome with elevated VEGFA, CCL11, MMP-10, and TRAIL. Monocytes exposed ex vivo to lenvatinib showed reduced production of IL-1β, IL-6, IL-8, and IL-10. In patients treated with lenvatinib, monocytes displayed increased IL-1Ra and TNF, while PBMCs exhibited enhanced IFN-γ production. Monocytes from healthy donors displayed reduced glycolysis and increased ROS after lenvatinib exposure. In TPC-1 cells, lenvatinib altered the secretome and upregulated MHC class I, PD-L1, and CD40.

Conclusions
Lenvatinib treatment has broad immunomodulatory effects in patients with TC, including shifts in immune cell populations, changes in the proteome, and reprogramming of cytokine responses. Lenvatinib also impacts monocyte metabolism and tumor cell phenotype. These findings provide insight into the multifaceted immunological activities of lenvatinib and highlight opportunities for treatment strategies.