Human natural killer (NK) cells have attracted widespread attention as a potential adoptive cell therapy (ACT). However, the therapeutic effects of NK cell infusion in patients with solid tumors are limited. There is an urgent need to explore a suitable new treatment plan to overcome weaknesses and support the superior therapeutic activity of NK cells.

In this study, the mechanisms underlying the susceptibility of gastric cancer (GC) cell lines AGS, HGC-27, and NCI-N87 to NK cell-mediated cytotoxicity were explored.

Lactic dehydrogenase (LDH) release assays showed that all three GC cell lines were susceptible to the umbilical cord blood NK (UCB-NK) cells, and HGC-27 cells with high CD56 expression were the most sensitive to UCB-NK, followed by NCI-N87 and AGS. When the expression of CD56 in HGC-27 cells decreased, the lytic activity of NK cells in HGC-27 cells was abating. In addition, combining oxaliplatin with NK cells produced additive anti-tumor effects in vitro, which may have resulted from oxaliplatin-induced NK group 2 member D (NKG2DL) upregulation in GC cells. These results of cytotoxicity activity showed that inhibition of CD56 expression might suppress the sensitivity of GC cells to NK cell-mediated cytotoxicity, and upregulation of the expression of NKG2DL on the surface of GC cells by oxaliplatin could enhance the killing sensitivity of NK cells.

Collectively, our study provides a deeper theoretical foundation and a better therapeutic strategy for NK cell immunotherapy in the treatment of human GC.