Study of Cytokine-Induced Memory-Like Natural Killer (CIML NK) cells as Possible Tool to Kill Non-Small Cell Lung Cancer (NSCLC) cells and to Contrast their Potential Tumorigenic Properties.

The overall aim of this study is to evaluate the antitumor ability of cytokine-induced memory like (CIML) NK cells in Non-Small Cell Lung Cancer (NSCLC), and ascertain whether their use could provide a functional advantage over conventionally activated NK cells currently employed in clinical trials. A comprehensive phenotypical analysis paired with a functional characterization of CIML NK cells showed that their differentiation was accompanied by an expansion of the CD56bright subset, and that this subset was the main driver of CIML NK effector functions, in terms of both cytotoxic degranulation and cytokine production. Compared to NK cells conventionally activated with IL-2 or IL-15, CIML NK cells displayed higher effector functions and, specifically, higher responsiveness and killing capabilities to NSCLC targets. CIML NK cells were also more effective than conventionally activated NK cells in targeting the CD133+ cell subpopulation within in vitro-generated NSCLC spheroids. This finding implies that CIML NK cells may significantly affect the tumorigenicity of NSCLC, as the cancer stem cell population is generally enclosed in the spheroid-derived CD133+ cells. Finally, we provide evidence that the ability of CIML NK cells to eliminate CD133+ NSCLC cells can be further enhanced by using a trispecific NK cell engager (TriKE) targeting CD133 on CSCs and engaging IL-15 receptor and CD16 on NK cells. In conclusion, we showed that CIML NK cells displayed a superior antitumor activity along with an enhanced capability in controlling tumorigenicity and stemness properties of malignant cells, and, more importantly, we also provide hints for more effective strategies to achieve a better NK cell targeting of tumor cells in NSCLC.