Surface nanotopography and cell shape modulate tumor cell susceptibility to NK cell cytotoxicity

Natural killer (NK) cells are innate cytotoxic lymphocytes exerting cytotoxicity against virally infected cells and tumor cells. NK cell cytotoxicity is primarily determined by biochemical signals received from ligands expressed on target cell surfaces, but it is also possible that biophysical environments of tumor cells, such as nanoscale surface topography typically existing on extracellular matrixes (ECMs) or cell morphology determined by ECM spaces or cell density, regulate NK cell cytotoxicity. In this study, micro/nanofabrication technology was applied to examine this possibility. Tumor cells were plated on flat or nanogrooved surfaces, or micropatterned into circular or elliptical geometries, and the effects of surface topography and tumor cell morphology on NK cell cytotoxicity were investigated. NK cells exhibited significantly higher cytotoxicity against tumor cells on nanogrooved surfaces or tumor cells in elliptical patterns than tumor cells on flat surfaces or tumor cells in circular patterns, respectively. The amounts of stress fiber formation in tumor cells positively correlated with NK cell cytotoxicity, indicating that increased cellular tension of tumor cells, either mediated by nanogrooved surfaces or elongated morphologies, was a key factor regulating NK cell cytotoxicity. These results may provide insight into the design of NK cell-based cancer immunotherapy.