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 CD81 T cells and NK cells in liver metastatic foci when combined with the anti (a)-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/a-GITR treatment also markedly promoted the maturation, activation and cytokine production of liver-resident macrophages and DCs compared with that achieved by a-GITR or Sunitinib treatment alone in mice. Cell depletion experiments demonstrated that CD8 1 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 1 T and NK cell response via inhibiting STAT3 activity.Thus, our findings provide a proof of concept that Sunitinib can synergize with a-GITR treatment to remodel the tumor immune microenvironment to trigger regressions of an established metastatic cancer.Renal cell carcinoma (RCC) is the most common form of kidney cancer, of which most patients present with localized RCC and can be cured with radical nephrectomy. 1,2 However, approximately 25 to 30% of patients will have metastatic RCC (mRCC) at diagnosis, and their long-term outcomes are generally dismal with an estimated 10% of 5-year survival rate.

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

“…The combination of antiangiogenic therapy and immunotherapy has been explored in a variety of pre-clinical models (Table 1) and forms the basis for a number of current clinical trials (Table 2). Much of the pre-clinical evidence relates to adoptive cell transfer and vaccination strategies, in combination with a wide variety of antiangiogenic therapies including VEGF-A blockade (97, 98, 111), VEGFR-2 blockade (100, 101), ligand traps (99, 112), receptor tyrosine kinase inhibitors (106, 107, 114, 115), irradiation (166), and angiostatic peptides (102, 103, 105, 113). For example, Shrimali et al demonstrated enhanced tumor infiltration, decreased tumor size, and improved survival when adoptive T cell transfer was combined with treatment with an anti-mouse VEGF-A antibody in a mouse model of melanoma (97).…”

The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies

“…70 Over the last decennia, anti-angiogenic drugs targeting the receptor-ligand interactions by monoclonal antibodies like bevacizumab or tyrosine kinase inhibitors were widely applied in clinical practice. Both act as tumor suppressors by promoting TAMs with an antitumor phenotype [71][72][73][74][75] or by decreasing monocyte recruitment. [76][77][78][79][80] This beneficial effect is partially compromised by activation of HIF-1α pathways that lead to an angiogenic counterresponse.…”

“…75 Tyrosine kinase inhibitors have more effects on immune cells. Erlotinib reportedly induces apoptosis of monocytic cell lines in vitro.…”

Suppression of immune regulatory cells with combined therapy of celecoxib and sunitinib in renal cell carcinoma

“…Recent study showed that sunitinib in combination with α-GITR could induce the significant infiltration of immune cells in tumor-metastatic liver, where the cell proliferation, activation and effector of CD8 + T cells and/or NK cells were extremely prominent [6]. The sequence of administration of immune treatment and targeted therapy is important.…”