title: 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.
authors.affiliation: Department of Urology, General Hospital of Jinan Military Command, Jinan, Shandong, China.
authors.forename: Nengwang
authors.initials: N
authors.lastname: Yu
authors.affiliation: Shandong Cancer Hospital & Institute, Shandong Academy of Medical Sciences, Jinan, 250117, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Urology, Qilu Hospital, Jinan, Shandong, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Urology, General Hospital of Jinan Military Command, Jinan, Shandong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Urology, General Hospital of Jinan Military Command, Jinan, Shandong, China.
authors.forename: Junwen
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Urology, General Hospital of Jinan Military Command, Jinan, Shandong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Oncology, General Hospital of Jinan Military Command, Jinan, Shandong, China.
authors.forename: Baocheng
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000819:agonists*; D007167:Immunotherapy / Q000379:methods*; D007211:Indoles / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib
chemical_list: D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: Sunitinib; anti-GITR; immunotherapy; metastatic renal cancer