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

Takanobu Motoshima, Yoshihiro Komohara, Hasita Horlad, ario takeuchi, Yoshihiro Maeda, Kenichiro Tanoue, Yoshiaki Kawano, Mamoru Harada, Motohiro Takeya, Masatoshi Eto

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2947-2953
Number of pages7
JournalOncology reports
Volume33
Issue number6
DOIs
Publication statusPublished - Jun 1 2015

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CTLA-4 Antigen
Antibodies
Neoplasms
Group Psychotherapy
Myeloid-Derived Suppressor Cells
Thomsen-Friedenreich antibodies
sorafenib
CD8-Positive T-Lymphocytes
Neoplasm Antibodies
T-Lymphocytes
Kidney Neoplasms
Therapeutics
Immunosuppressive Agents

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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.

In: Oncology reports, Vol. 33, No. 6, 01.06.2015, p. 2947-2953.

Research output: Contribution to journalArticle

Motoshima, Takanobu ; Komohara, Yoshihiro ; Horlad, Hasita ; takeuchi, ario ; Maeda, Yoshihiro ; Tanoue, Kenichiro ; Kawano, Yoshiaki ; Harada, Mamoru ; Takeya, Motohiro ; Eto, Masatoshi. / Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells. In: Oncology reports. 2015 ; Vol. 33, No. 6. pp. 2947-2953.
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