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

被引:20
|
作者
Motoshima, Takanobu [1 ,2 ]
Komohara, Yoshihiro [2 ]
Horlad, Hasita [2 ]
Takeuchi, Ario [3 ]
Maeda, Yoshehiro [1 ]
Tanoue, Kenichiro [1 ]
Kawano, Yoshiaki [1 ]
Harada, Mamoru [4 ]
Takeya, Motohiro [2 ]
Eto, Masatoshi [1 ]
机构
[1] Kumamoto Univ, Dept Urol, Grad Sch Med Sci, Kumamoto 8608556, Japan
[2] Kumamoto Univ, Dept Cell Pathol, Grad Sch Med Sci, Kumamoto 8608556, Japan
[3] Kyushu Univ, Dept Urol, Grad Sch Med Sci, Fukuoka, Japan
[4] Shimane Univ, Fac Med, Dept Immunol, Izumo, Shimane, Japan
关键词
anti-CTLA-4; antibody; myeloid-derived suppressor cells; combination therapy; renal cell carcinoma; METASTATIC MELANOMA; JAPANESE PATIENTS; PROGNOSTIC-FACTORS; INTERFERON-ALPHA; TARGETED THERAPY; CARCINOMA; IPILIMUMAB; BLOCKADE; SURVIVAL; TRIAL;
D O I
10.3892/or.2015.3893
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:2947 / 2953
页数:7
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