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

Abstract

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. What's new? Sunitinib is an oral multitargeted tyrosine kinase inhibitor able to inhibit tumor growth directly by promoting tumor apoptosis and inhibiting tumor angiogenesis, and indirectly by stimulating anti-tumor immune responses. This study demonstrates that sequential treatment with Sunitinib and α-GITR antibody can produce a potently synergistic antitumor efficacy in a murine mRCC model, by rewiring effector functions of tumor-associated macrophages and inducing CD8+ T and NK cell responses. As immune-stimulatory monoclonal antibodies including α-GITR are undergoing clinical trials, these data support the potential use of combined Sunitinib/α-GITR in mRCC therapy, which may be particularly beneficial in cancers previously responsive to Sunitinib.