Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells

Motoshima,Takanobu; Komohara,Yoshihiro; Horlad,Hasita; Takeuchi,Ario; Maeda,Yoshihiro; Tanoue,Kenichiro; Kawano,Yoshiaki; Harada,Mamoru; Takeya,Motohiro; Eto,Masatoshi

doi:10.3892/or.2015.3893

Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells

Authors:
- Takanobu Motoshima
- Yoshihiro Komohara
- Hasita Horlad
- Ario Takeuchi
- Yoshihiro Maeda
- Kenichiro Tanoue
- Yoshiaki Kawano
- Mamoru Harada
- Motohiro Takeya
- Masatoshi Eto
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Affiliations: Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, Department of Urology, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan, Department of Immunology, Shimane University Faculty of Medicine, Izumo, Japan
Published online on: April 2, 2015 https://doi.org/10.3892/or.2015.3893
Pages: 2947-2953

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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.

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