title: Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells.
abstract: This antitumor effect of sorafenib is considered to be dependent not only on its direct cytotoxicity to cancer cells but also due to the inhibition of myeloid-derived suppressor cells (MDSCs). Recently, a novel antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), which activates lymphocytes, is currently in clinical applications. The aim of the present study was to investigate the synergistic antitumor effects of anti-CTLA-4 antibody (Ab) and sorafenib in a murine cancer model. RENCA cells were subcutaneously inoculated into mice, which were randomly divided into 4 treatment groups: sorafenib plus anti-CTLA-4 Ab, sorafenib plus control Ab, vehicle plus anti-CTLA-4 Ab, and vehicle plus control Ab. Single therapy using anti-CTLA-4 Ab suppressed tumor growth, but no difference was noted when compared with the single therapy group using sorafenib. Notably, the greatest decrease in tumor size was noted with sorafenib plus anti-CTLA-4 Ab (combination therapy), and the highest rate of tumor rejection was observed in the combination therapy group. The number of infiltrating CD4- or CD8-positive lymphocytes was strongly increased in the combination therapy group. These in vivo data indicate that sorafenib increased the immunostimulatory effect of anti-CTLA-4 Ab even when sorafenib was used at a low dose. An in vitro study using MDSCs and CD8(+) T cells showed that the inhibitory effect of MDSCs on CD8(+) T cells was significantly abrogated by the combined use of sorafenib and anti-CTLA-4 Ab. Sorafenib suppressed the expression of immunosuppressive factors in MDSCs. These data indicate that combination therapy of sorafenib and anti-CTLA-4 Ab may be effective in advanced kidney cancer patients.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Motoshima
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hasita
authors.initials: H
authors.lastname: Horlad
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan.
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Tanoue
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Immunology, Shimane University Faculty of Medicine, Izumo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Eto
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib
chemical_list: D000888:Antibodies, Anti-Idiotypic; D060908:CTLA-4 Antigen; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib