NK cells in the brain: implications for brain tumor development and therapy

Natural killer (NK) cell therapies are finding their way as promising tools for more effective treatment of brain tumors. Their unique physiology makes NK cells particularly suited for this role, offering two major advantages: independence from antigen presentation by MHC molecules, and safety for allogeneic use. Advances in culturing techniques, supplying combinations of growth factors and/or engineered feeder layer cells, support vigorous NK cell expansion. These approaches offer the advantages of an off-the-shelf product, easier to genetically engineer without compromising treatment efficacy. NK cells demonstrated good safety but modest clinical activity. The concurrent application of traditional and innovative strategies, such as specific antigen targeting with chimeric antigen receptors (CARs), stimulation with activating cytokines, creation of small bispecific and trispecific killer cell engager (BiKE and TriKE) multidomain molecules, and sensitization of malignant cells through combinatorial treatments, offers new avenues to achieve better efficacy. In contrast to CAR-T cells, NK cells lend themselves to off-the-shelf applications owing to their favorable safety profile and retained efficacy in an allogeneic setting. Thus, they promise benefits in terms of treatment standardization, timeliness, and cost. Natural killer (NK) cells are innate lymphoid cells with robust antitumor functions rendering them promising therapeutic tools against malignancies. Despite constituting a minor fraction of the immune cells infiltrating tumors in the brain, insights into their role in central nervous system (CNS) pathophysiology are emerging. The challenges posed by a profoundly immunosuppressive microenvironment as well as by tumor resistance mechanisms necessitate exploring avenues to enhance the therapeutic potential of NK cells in both primary and metastatic brain malignancies. In this review, we summarize the role of NK cells in the pathogenesis of tumors in the brain and discuss the avenues investigated to harness their anticancer effects against primary and metastatic CNS tumors, including sources of therapeutic NK cells, combinations with other treatments, and novel engineering approaches for augmenting their cytotoxicity. We also highlight relevant preclinical evidence and clinical trials of NK cell-based therapies. Natural killer (NK) cells are innate lymphoid cells with robust antitumor functions rendering them promising therapeutic tools against malignancies. Despite constituting a minor fraction of the immune cells infiltrating tumors in the brain, insights into their role in central nervous system (CNS) pathophysiology are emerging. The challenges posed by a profoundly immunosuppressive microenvironment as well as by tumor resistance mechanisms necessitate exploring avenues to enhance the therapeutic potential of NK cells in both primary and metastatic brain malignancies. In this review, we summarize the role of NK cells in the pathogenesis of tumors in the brain and discuss the avenues investigated to harness their anticancer effects against primary and metastatic CNS tumors, including sources of therapeutic NK cells, combinations with other treatments, and novel engineering approaches for augmenting their cytotoxicity. We also highlight relevant preclinical evidence and clinical trials of NK cell-based therapies. a type of therapy involving the administration of immune cells to a patient. the process whereby IgG-opsonized abnormal cells undergo NK cell-mediated lysis via engagement of CD16 (FcγRIIIA) on NK cells. the central cell type of the humoral branch of the adaptive immune system whose key function is the production of antigen-specific immunoglobulins. the system composed by the microvasculature of the central nervous system that tightly regulate the movement of molecules, ions, and cells between the blood and the central nervous system. It is established by capillary endothelial cells and held together by tight junctions. small molecules designed to engage NK cells against cancer cells so that the latter undergo NK cell-mediated lysis. A BiKE consists of a tumor-associated antigen (TAA)-specific scFv coupled with an NK cell-specific scFv, while the incorporation of an additional TAA-specific scFv or a cytokine into the structure leads to the creation of a TriKE. T and NK cells engineered to express CAR molecules are referred to as CAR-T and CAR-NK cells, respectively. CAR molecules are composed of an extracellular antigen-recognizing moiety, a transmembrane domain, and an intracellular signaling region often coupled with one or two costimulatory domains. The engagement of the antigen activates the CAR-bearing immune cell against the designated target. the maintenance of the normal state of function of the central nervous system, which requires tight regulation of immune activity within its boundaries. the pathway that senses genotoxic stress and responds by arresting the cell cycle, activating DNA repair mechanisms, inducing expression of NK cell activating ligands, or initiating apoptosis. a population of glioblastoma cells that sustains tumor growth and confers resistance to conventional treatments. protein belonging to the transforming growth factor beta superfamily which exert immune evasive effects in gliomas. functional ligand for the NK cell inhibitory receptor CD161. are effector cells obtained from ex vivo culture of fresh lymphocytes in the presence of IL-2, and their cytotoxic activity is mainly mediated by the NK cell fraction of the preparation. cell surface molecules belonging to the family of major histocompatibility complex. They are present on the majority of nucleated cells and can be divided into the polymorphic, peptide-presenting classical MHC class I molecules (HLA-A, HLA-B, HLA-C) and the relatively nonpolymorphic, NK cell-regulating nonclassical MHC class I molecules (HLA-E, HLA-G). the yolk sac-derived tissue-resident macrophages of the central nervous system, in which they settle during embryonic development and constitute the predominant form of myeloid cells. immature cells of myeloid origin that are found in abnormally high frequency in the peripheral blood of patients with various pathologies, including many malignancies, and exert immunosuppressive functions in the tumor microenvironment, particularly of glioblastoma. innate lymphoid cells that patrol the organism for stressed, infected, foreign, or neoplastic cells and respond promptly with direct cytotoxicity as well as secretion of cytokines. the therapeutic administration of a virus that selectively infects and lyses malignant cells, thereby triggering a robust antitumor immune response. V-ATPase protein that regulates ATP levels in a variety of cells. the main cell type of the cell-mediated branch of the adaptive immune system. They express antigen receptors for peptides presented by MHC molecules and are traditionally divided into cytotoxic T cells (CD8+) and cytokine-producing helper T cells (CD4+). macrophages in the tumor microenvironment. In brain tumors, they are derived from microglia and circulating monocytes, and tend to exhibit an anti-inflammatory and pro-tumorigenic phenotype. the normal cells, molecules, and blood vessels that surround and support a tumor cell. A tumor influence the microenvironment, and the microenvironment can affect how a tumor grows and spreads. regulatory T cells are a specialized subpopulation of T cells that act to suppress immune response, thereby maintaining homeostasis and self-tolerance.