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

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.