Relevance of target cell-induced apoptosis as mechanism of resistance against natural killer cells

Natural killer (NK) cells contribute to the graft-versus-leukemia effect after allogeneic stem cell transplantation. However, the efficacy of NK cell-mediated tumor cell lysis is limited due to target cell resistance, and target cell-induced apoptosis (TiA) was proposed to contribute to differences in susceptibility to NK cells. Here we analyzed the effects of target cells on the apoptosis of cytokine-activated NK cells in vitro. We found no association of target cell susceptibility and TiA of NK cells in an array of human and murine target-effector cell combinations. Incubation of NK cells with caspase inhibitors blocked TiA incompletely, indicating that TiA is partly based on caspase-independent mechanisms. Modulating NK cell susceptibility against TiA by caspase inhibition did not influence cytotoxic efficacy. Furthermore, we found cytotoxic potential of NK cells to be markedly decreased following first target cell contact. Exhaustion of NK cell activity by first target cell contact was, however, not mediated by TiA. In addition, we found no relevant TiA by lymphoma cell lines against activated murine NK cells. We conclude that TiA represents only a minor factor of target cell resistance against NK cell-mediated cytolysis.