Immunologic effects of sunitinib in renal cell carcinoma

Abstract

14551 Background: Sunitinib is a multi-targeted tyrosine kinase inhibitor with proven efficacy against renal cell carcinoma (RCC). Sunitinib demonstrates immunomodulatory characteristics which may potentially augment the potency of tumor vaccines. We examined the effect of sunitinib therapy on measures of cellular immunity and its ability to reverse tumor associated immune suppression mediated by regulatory T cells (Tregs) and the inhibitory molecule PD-L1 (programmed cell death ligand-1). Methods: Peripheral blood was collected in RCC patients pre- and post-sunitinib therapy. Phenotypic and functional characteristics of circulating T cells and dendritic cells (DC) were determined. Levels of Tregs (CD4+/CD25+/FOXP3+) were quantified. In vitro effects of sunitinib on the expression PD-L1 by RCC were assessed by flow cytometry and western blot analysis. Results: A significant increase in T cell activity was observed after one month of sunitinib therapy as manifested by enhanced proliferative responses to phytohemagglutinin (1.7 fold, p=0.05), allogeneic DCs (2.8 fold) and tetanus toxoid (3.7 fold). However, T cell proliferation was not enhanced by direct exposure to sunitinib in vitro. Sunitinib therapy resulted in a 2.5 fold decrease (p=0.03) in circulating levels of Tregs. In vitro exposure of RCC cell lines to sunitinib resulted in significant depression of PD-L1 expression (11.6 fold decrease in % and 2.5 fold decrease in MFI, p=0.004). In contrast, an increase was seen after exposure to sorafenib. A decrease in PD-L1 expression in RCC tumors treated with sunitinib was also seen in a mouse xenograft model. Coculture of sunitinib with the DC/RCC fusion vaccine resulted in increased capacity to stimulate T cell proliferation (mean stimulation index of 9.5) as compared to fusions alone (mean SI 3.7) and sunitinib alone (mean SI 1.2). Sunitinib exposure also resulted in an increase in fusion mediated stimulation of T cell IFNγ expression. Conclusions: Sunitinib therapy augments measures of T cell immunity by modulating immunosuppressive factors. Levels of Tregs are decreased in vivo and RCC expression of PD-L1 is decreased in vitro. Sunitinib enhances the potency of the DC/RCC fusion vaccine in vitro. These experiments lay the groundwork for a clinical trial of sunitinib with a DC based vaccine in patients with RCC. No significant financial relationships to disclose.