Targeting natural killer cells and natural killer T cells in cancer

Abstract

Natural killer (NK) cells and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities. Both cell types can rapidly respond to the presence of tumour cells and participate in antitumour immune responses. This has prompted interest in the development of innovative cancer therapies that are based on the manipulation of NK and NKT cells. Recent studies have highlighted how the immune reactivity of NK and NKT cells is shaped by the environment in which they develop. The rational use of these cells in cancer immunotherapies awaits a better understanding of their effector functions, migratory patterns and survival properties in humans.

Figure 1

NK cell recognition of tumour cells. a | NK cells are tolerant to normal self cells as the ‘strength’ of activating signals is dampened by engagement of inhibitory receptors. b | NK cells are selectively activated by stressed cells as they express a density of cell surface ligands for activating receptors which overcomes signalling via inhibitory receptors. c | this NK cell activation leads to tumour elimination directly (cytotoxicity) or indirectly (production of cytokines such as IFN-γ).

Figure 2

NK cellular therapy. a | In haplo-identical or MHC-matched HSCT, NK cells of healthy donor origin will develop into the cancer patient. b | Alternatively, NK cells can be isolated from healthy donors, activated and/or expanded in vitro prior to infusion into the cancer patient. In both cases (allo-HSCT and NK cell infusions), the aim is to promote the anti-tumour function of donor NK cells in the cancer patient; indeed a fraction of donor NK cells will be not be inhibited by the MHC class I molecules of the cancer patient as the KIR expressed by these subsets of NK cells will not interact with by the MHC class I molecules of the cancer patient (ELIMINATION). Most normal cells of the patients will not activate donor NK cells as, in contrast to cancer cells of the patient, they lack the cell surface density of ligands required to activate donor NK cells (IGNORANCE). c | Anti-KIR monoclonal antibody therapy. Fully human anti-KIR mAbs can be injected in cancer patient. Anti-KIR mAbs are designed to boost the antitumour activity of NK cells (ELIMINATION) without inducing auto-immunity (IGNORANCE).

Figure 3

iNKT cell recognition of tumours. a | normal and direct recognition of tumour cells by iNKT cells. b | Indirect activation and indirect killing mediated by iNKT cells. c | Control of angiogenesis by iNKT cells

Figure 4

iNKT cellular therapy. Patient Specific iNKT cell subset expanded in vitro prior to infusion together with CD1d ligand pulsed Dendritic cells.