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 (α)‐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/α‐GITR treatment also markedly promoted the maturation, activation and cytokine production of liver‐resident macrophages and DCs compared with that achieved by α‐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 α‐GITR treatment to remodel the tumor immune microenvironment to trigger regressions of an established metastatic cancer.