CD48-expressing non-small-cell lung cancer cells are susceptible to natural killer cell–mediated cytotoxicity

The susceptibility of cancer cells to natural killer (NK) cell–mediated cytotoxicity depends on the balance of activating and inhibitory ligands expressed on their surface. Although many types of cancer cells are killed by NK cells, non-small-cell lung cancer (NSCLC) cells are relatively resistant to NK cell–mediated cytotoxicity. In this study, we showed that several NSCLC cell lines have differential sensitivity to NK cell–mediated cytotoxicity: NCI-H522 cells were highly sensitive, but A549, NCI-H23, NCI-H1915, and NCI-H1299 were resistant. Among activating ligands such as CD48, HLA-A/B/G, ICAM-1, MICA/B, and ULBPs, only CD48 rendered NCI-H522 cells susceptible to NK cell–mediated cytotoxicity, which was proved by using CD48 siRNA and neutralizing antibody. CD48-positive NCI-H522 cells established a more stable contact with NK cells than did CD48-negative A549 and CD48 siRNA cell–transfected NCI-H522 cells. Taken together, these data demonstrate that CD48-positive NSCLC cells might be susceptible to NK cell–mediated cytotoxicity, which provide information on how to stratify NSCLC patients potentially responsive to NK-cell therapy.