Synergistic antitumor responses by combined GITR activation and sunitinib in metastatic renal cell carcinoma

Sunitinib, a multitargeted tyrosine kinase inhibitor, is the frontline therapy for renal and gastrointestinal cancers. In view of its well-documented proapoptotic and immunoadjuvant properties, we speculate that combination of Sunitinib and immunotherapy would provide a synergistic antitumor effect. Here, we report that a remarkably synergistic antitumor responses elicited by the combined treatment of Sunitinib and an agonistic antibody against glucocorticoid-induced TNFR related protein (GITR) in a model of metastatic renal cell carcinoma. Sunitinib significantly increased the infiltration, activation, and proliferation and/or cytotoxicity of CD8(+) T cells and NK cells in liver metastatic foci when combined with the anti (alpha)-GITR agonist, which was associated with treatment-induced prominent upregulation of Th1-biased immune genes in the livers from mice receiving combined therapy versus single treatment. Sunitinib/alpha-GITR treatment also markedly promoted the maturation, activation and cytokine production of liver-resident macrophages and DCs compared with that achieved by alpha-GITR or Sunitinib treatment alone in mice. Cell depletion experiments demonstrated that CD8(+) T cells, NK cells and macrophage infiltrating liver metastatic foci all contribute to the antitumor effect induced by combined treatment. Furthermore, mechanistic investigation revealed that Sunitinib treatment reprograms tumor-associated macrophages toward classically activated or "M1" polarization upon GITR stimulation and consequently mounts an antitumor CD8(+) T and NK cell response via inhibiting STAT3 activity. Thus, our findings provide a proof of concept that Sunitinib can synergize with alpha-GITR treatment to remodel the tumor immune microenvironment to trigger regressions of an established metastatic cancer.