Overcoming Resistance to Checkpoint Inhibitors: Natural Killer Cells in Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatments over the last 10 years, with even increasing indications in many neoplasms. Non-small cell lung cancer (NSCLC) is considered highly immunogenic, and ICIs have found a wide set of applications in this area, in both early and advanced lines of treatment, significantly changing the prognosis of these patients. Unfortunately, not all patients can benefit from the treatment, and resistance to ICIs can develop at any time. In addition to T lymphocytes, which are the major target, a variety of other cells present in the tumor microenvironment (TME) act in a complex cross-talk between tumor, stromal, and immune cells. An imbalance between activating and inhibitory signals can shift TME from an "anti-" to a "pro-tumorigenic" phenotype and vice versa. Natural killer cells (NKs) are able to recognize cancer cells, based on MHC I (self and non-self) and independently from antigen presentation. They represent an important link between innate and adaptive immune responses. Little data are available about the role of pro-inflammatory NKs in NSCLC and how they can influence the response to ICIs. NKs express several ligands of the checkpoint family, such as PD-1, TIGIT, TIM-3, LAG3, CD96, IL1R8, and NKG2A. We and others have shown that TME can also shape NKs, converting them into a pro-tumoral, pro-angiogenic "nurturing" phenotype through "decidualization." The features of these NKs include expression of CD56, CD9, CD49a, and CXCR3; low CD16; and poor cytotoxicity. During ICI therapy, tumor-infiltrating or associated NKs can respond to the inhibitors or counteract the effect by acting as pro-inflammatory. There is a growing interest in NKs as a promising therapeutic target, as a basis for adoptive therapy and chimeric antigen receptor (CAR)-NK technology. In this review, we analyzed current evidence on NK function in NSCLC, focusing on their possible influence in response to ICI treatment and resistance development, addressing their prognostic and predictive roles and the rationale for exploiting NKs as a tool to overcome resistance in NSCLC, and envisaging a way to repolarize decidual NK (dNK)-like cells in lung cancer.