The combination therapy of [alpha]-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice

[alpha]-Galactosylceramide ([alpha]-GalCer) has been reported to be therapeutic against metastatic liver tumors in mice. However, little is known regarding the efficacy of combined chemo-immunotherapy using [alpha]-GalCer and anticancer drugs. In this study, we evaluated the antitumor effect of the combination therapy of [alpha]-GalCer and 5-fluorouracil (5-FU) against liver tumors of MC38 colon cancer cells. The liver weights of tumor-bearing mice treated with the combination were significantly lower than those of nontreated mice and of mice treated with 5-FU or [alpha]-GalCer alone. No toxic effects on the liver and renal functions were observed in any of the treatment groups. [alpha]-GalCer treatment induced significant activation of liver NK cells in vivo, but 5-FU treatment did not. 5-FU treatment resulted in a significant upregulation of NKG2D activating molecules (Rae-1 and H60) and DNAM-1 ligands (CD112 and CD155) on MC38 cells, but [alpha]-GalCer did not. The cytolytic activity of [alpha]-GalCer-activated liver mononuclear cells against 5-FU-treated MC38 cells was significantly higher than that against nontreated cells. The increase of the cytolytic activity induced by 5-FU partially depended on NKG2D-Rae-1 or H60 signals. Depletion of NK cells significantly inhibited the antitumor efficacy of 5-FU against MC38 liver tumors, which suggested that the antitumor effect of 5-FU partially depended on the cytolytic activity of NK cells. These results demonstrated that the combination therapy of [alpha]-GalCer and 5-FU produced synergistic antitumor effects against liver tumors by increasing the expression of NK activating molecules on cancer cells. This study suggests a promising new chemo-immunotherapy against metastatic liver cancer. What's new? [alpha]-Galactosylceramide ([alpha]-GalCer) is effective against metastatic liver tumors in mice. In this study, the authors evaluated the antitumor effect of a combination therapy of [alpha]-GalCer plus 5-FU. They found that the combination therapy produced synergistic antitumor effects against liver tumors of colon cancer cells in mice, by both increasing the activation of natural killer (NK) cells and enhancing the sensitivity of the cancer cells to those NK cells. This combination may therefore represent a promising new chemo-immunotherapy against metastatic liver cancer. [PUBLICATION ABSTRACT]