Prashant Changoer¹, Peng Chunying¹, Pepijn van Houten¹, Martin Jaeger¹, Liesbeth van Emst¹, Janneke Walraven², Petronella Ottevanger², Romana Netea-Maier¹


(1) Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. 

(2) Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.

Rationale:

Aggressive thyroid cancers (TC) are densely infiltrated by immunosuppressive monocytes and macrophages, correlating with a poor prognosis. Preclinical studies indicate that Lenvatinib, a multi-target kinase inhibitor approved for treatment of TC, has immunomodulatory influences on myeloid cells from healthy donors that could contribute to its anti-tumoral effects. This study aims to comprehensively investigate the functional and metabolic signature of circulating myeloid cells in patients with TC treated with Lenvatinib.

Methods:

Whole blood was collected from 30 patients with advanced metastatic TC, of which 15 using Lenvatinib for a median of 2.8 months and 15 not treated with Lenvatinib. Monocytes were isolated and their cytokine production capacity was assessed after ex vivostimulation with lipopolysaccharide (LPS) in the presence and absence of Lenvatinib. Cytokine and lactate concentrations were measured in supernatants. In healthy donors, functional exploratory experiments were performed including ROS assays and seahorse metabolic assays.

Results:

Monocytes of patients using Lenvatinib had an increased production of the anti-tumor cytokine IL-1RA upon LPS stimulation compared with those from patients not receiving Lenvatinib.  Ex vivo Lenvatinib exposure of treatment naïve patients monocytes highly attenuated their capacity to produce IL-1β, IL-8, IL-6, IL-10 and TGF-β upon LPS stimulation. Moreover, ex vivo Lenvatinib exposure lowered lactate production in patient samples, consistent with reduced glycolysis rates in healthy donors monocytes. Finally, Lenvatinib increased cytotoxic ROS production.

Conclusion:

In patients with advanced TC, Lenvatinib treatment modulates anti-tumor immune responses by altering cytokine production capacity, potentially reversing some immunosuppressive properties of myeloid cells, and increasing their cytotoxic capacity. These immunomodulatory effects can potentiate the anti-tumoral effects of Lenvatinib and could be further explored therapeutically in future studies.