Natural Killer Cells: Angels and Devils for Immunotherapy

Abstract

In recent years, the relevance of the immune system to fight cancer has led to the development of immunotherapy, including the adoptive cell transfer of immune cells, such as natural killer (NK) cells and chimeric antigen receptors (CAR)-modified T cells. The discovery of donor NK cells’ anti-tumor activity in acute myeloid leukemia patients receiving allogeneic stem cell transplantation (allo-SCT) was the trigger to conduct many clinical trials infusing NK cells. Surprisingly, many of these studies did not obtain optimal results, suggesting that many different NK cell parameters combined with the best clinical protocol need to be optimized. Various parameters including the high array of activating receptors that NK cells have, the source of NK cells selected to treat patients, different cytotoxic mechanisms that NK cells activate depending on the target cell and tumor cell survival mechanisms need to be considered before choosing the best immunotherapeutic strategy using NK cells. In this review, we will discuss these parameters to help improve current strategies using NK cells in cancer therapy. Moreover, the chimeric antigen receptor (CAR) modification, which has revolutionized the concept of immunotherapy, will be discussed in the context of NK cells. Lastly, the dark side of NK cells and their involvement in inflammation will also be discussed.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…As aforementioned, NK cells can also exhibit potent anti-tumor function and their activity is modulated by an array of inhibitory and activating receptors [198]. Because of their cytotoxic capacity, a few studies have also examined the potential of NK lymphocytes to serve as a cellular platform for CARs (reviewed in [336]).…”

“…NCR ligands can also regulate the receptor function and may facilitate tumor escape from NK cells [195][196][197], which would support their extensive expression by tumor cells. Although usage of NK-based immunotherapies is currently limited by poor expansion and endogenous inhibitory mechanisms [198], one way to combine the tumor recognition capability of NK cells with T cell effectiveness and flexibility is to design CARs based on the EC domain of NCRs. Thus, we and others showed that NCR1 [199], NCR2 [105] and NCR3 [200] based chimeric receptors can mediate the recognition of several types of tumors (e.g.…”

Natural Killer Cell-Mediated Cellular Therapy of Hematological Malignancies

“…Although PD-1 antibodies, including pidilizumab, lambrolizumab, and nivolumab mainly target T cells and provide tumor suppression, they also may boost endogenous NK cell functions [51]. NK cell cytotoxicity can also be enhanced and redirected to tumor cells via bi-or tri-specific engagers [52][53][54]. These monoclonal antibodies may be combined with other treatments, particularly NK-stimulating cytokines, in order to produce synergistic effects.…”

Immune Regulatory Network in Cervical Cancer Development: The Expanding Role of Innate Immunity Mechanisms

“…Unlike neutrophils and suppressor populations of myeloid cells, whose contribution to the progression of solid tumors has only recently come under intense investigation, the functions of natural killer cells have always been considered in the context of cancer immunosurveillance. However, in spite of the fact that for this group of innate lymphoid cells, a detailed spectrum of receptors allowing for recognition of transformed cells has been described and a vast diversity of mechanisms for their cytotoxic action has been established, attempts to use them in anticancer therapy occurred to be unsuccessful-the reasons for this situation are reviewed in [41], and among these reasons are the underappreciated regulatory properties of NK cells implementing via production of a wide range of cytokines, the specificity of which is largely determined by the surrounding molecular context. Nevertheless, recently there has been considerable revival of interest in NK cells brought about by the invention of chimeric antigen receptors (CAR) technology that made possible creation of engineered CAR-NKs with "improved" properties (e.g., increased migrating and proliferating ability, up-regulated expression of activating receptors) for their subsequent adoptive transfer into a cancer patient.…”