Our recent data in the context of non-small cell lung malignancy (NSCLC) supports this hypothesis (66)

Our recent data in the context of non-small cell lung malignancy (NSCLC) supports this hypothesis (66). control of malignancy and malignancy stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of malignancy angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention including NK cells as a target or an ally in oncology. Natural killer (NK) cells, the first innate lymphoid cells discovered, are the most widely distributed and were originally described as large granular lymphocytes able to lyse tumor cells without requiring prior activation (1). NK cell biology is quite complex and has been reviewed in detail elsewhere (2C4); here we discuss the role of NK cells in angiogenesis, tumor tolerance, and progression. Two major subsets of peripheral blood NK cells have been recognized in humans, on the basis of surface density expression of CD56, an isoform of the human neural cell adhesion molecule, and of CD16, the low-affinity Fc receptor. The CD56dimCD16+ NK cell subset constitutes about 90C95% of peripheral blood NKs that show higher amounts of cytolytic granules, such as perforin and granzyme, and are cytotoxic when encountering nonself (observe below) or mediating antibody-dependent cell cytotoxicity (ADCC) (5). Although poor long-term cytokine suppliers, these cells have recently been shown to rapidly (2 to 4 hours) release substantial amounts of cytokines (6,7). The other relevant peripheral blood NBQX NK cell subset is usually CD56brightCD16-/low cells NBQX (about 5C10% of peripheral blood NKs). While weakly cytotoxic, they can produce large amounts of some cytokines, including IFN, TNF, and GM-CSF. The CD56brightCD16-/low cells are considered critical for development of type 1 T-cell responses, since they provide an important innate source of interferon (IFN), conditioning the microenvironment during antigen presentation in secondary lymphoid organs Neurog1 (8) as well as for other immune reactions. The cytokine-producing CD56brightCD16-/low NK cells are recognized as NK cells that have not yet reached a terminal differentiation into cytotoxic NK cells. These cells can undergo further maturation upon exposure to specific cytokines (interleukin [IL]-2, IL-12, and/or IL-15) into CD56dimCD16+ cells, displaying higher levels of perforin and more effective cytolytic capability (9,10). The acquisition of NK cell cytotoxicity during development has been associated with development of highly sophisticated and robust mechanisms controlling NK cytolysis in order to avoid tissue damage. Cytolysis is activated through a variety of cell surface receptors that modulate NK cell functions (11C14). Current data are compatible with the concept that this ligands for activating NK receptors are expressed primarily by stressed cells (including tumor- or virus-infected cells). NKp46, NKp30, and NKp44 are activating receptors that have been NBQX collectively named natural cytotoxicity receptors (NCRs). They NBQX were the first human activating receptors mediating NK cytotoxicity to be recognized and molecularly characterized (14). Although NBQX some viral glycoproteins have been found to bind to NCRs (15), the tumor ligands for NK cells are not fully defined. B7-H6 and, very recently, a novel isoform of the mixed-lineage leukemia (MLL5) protein have been recognized that bind to NKp30 and NKp44, respectively, and are expressed on a large panel of tumors (16C19). A direct association has been established between the surface density of NCR on NK cells and the intensity of NK-mediated anti-tumor cytolytic activity (20). NKG2D is usually a different type of NK-activating receptor that is expressed also by cytotoxic T lymphocytes. NKG2D recognizes the stress-inducible MHC class I chain-related A and B genes (MICA/B) (21) and UL16-binding protein (ULBP) proteins (22). Lastly, it has been demonstrated that DNAM-1 (DNAX accessory molecule-1), a triggering receptor expressed by virtually all NK cells (but also by T-lymphocyte subsets and monocytes), is able to specifically bind CD155 and Nectin-2 (CD112), two members of the nectin family present on most tumor cell.