Susceptibility of ovarian cancer stem cells to anti-cancer drugs and natural killer cells

Abstract

Natural killer cells are lymphocytes of the innate immune system that play a key role in the direct elimination of transformed or virus-infected cells. Recently, it has been reported that NK cells can attack cancer cells with stem cell-like properties. In this study, we isolated ovarian cancer cell lines CAOV3, TOV21G, and TOV112D with and without the ovarian cancer stem cell marker CD24 and compared their drug resistance and susceptibility to NK cell lysis. The isolated CD24+ CAOV3, TOV21G, and TOV112D cells were more resistant to cisplatin and doxorubicin antitumor drugs. Also, CD24+ CAOV3 and TOV21G cells were more susceptible to NK cell lysis compared with CD24- cells, whereas CD24+ TOV112D cells showed the opposite result. In order to identify reasons for the differing NK cell susceptibility, we examined NK cell-killing mechanisms against CD24+ cancer cell lines by analyzing NKG2D ligands, natural cytotoxic receptor ligands, Fas, and TRAIL receptor expression on target cells. Consistently, CD24+ CAOV3 and TOV21G cells showed up-regulated NKG2D ligands and down-regulated MHC class I molecule expression, whereas CD24+ TOV112D showed the opposite results. To investigate the inconsistent results of TOV112D cells, we measured CD44 cell surface expression and showed that CD44 expression with CD24 might be critical to the expressions of cancer stem cell properties. These findings show that cancer stem cells are more resistant to antitumor drugs but are more susceptible to NK cell lysis; thus, NK cell immunotherapy might be useful in eliminating ovarian cancer stem cells and preventing tumor recurrence and metastasis.