Use of natural killer cells as immunotherapy for leukaemia

Abstract

Natural killer (NK) cells potentially play a significant role in eradicating residual disease following allogeneic haematopoietic cell transplantation, and have been explored as tools for adoptive immunotherapy for chemotherapy-refractory patients. NK cell cytotoxicity is modulated by multiple activating and inhibitory receptors that maintain a balance between self-tolerance and providing surveillance against pathogens and malignant transformation. The functional characteristics of NK cells are dictated by the strength of inhibitory receptor signalling. Major histocompatibility complex (MHC)-specific inhibitory receptor acquisition occurs sequentially during NK cell development, and is determined by the nature of immunological reconstitution after allogeneic haematopoietic cell transplantation. Polymorphisms of inhibitory receptors [killer immunoglobulin-like receptors (KIRs)] and their ligands (MHC) contribute to interindividual variability. As a result, the functional NK cell repertoire of individual donors has variable potential for graft-vs-leukaemia reactions. Models predicting NK cell alloreactivity, including KIR ligand mismatch and missing KIR ligand strategies, are discussed as algorithms for optimal NK cell donor selection. Future modifications to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signalling are being explored.

Figure 1

Human leukocyte antigen (HLA) type of the donor affects natural killer (NK) cell repertoire and thereby alloreactive potential of NK cells. Exemplified by two donors, one with a single functional killer immunoglobulin-type receptor (KIR)–HLA pair (2DL1– HLA C2), the other with five KIR–HLA pairs (3DL– HLA Bw4, 2DL1–HLA C2, 2DL2–HLA C1, 2DL3–HLA C1 and 3DL2–HLA A3/A11). In the NK repertoire of such donors, the relative contribution of NK cells expressing KIRs for which there is an HLA ligand (filled black) or expressing KIRs for which there are no ligands (empty) is different (depicted by arrows as relative increase or decrease). The majority of NK cells expressing no functional KIRs (or expressing KIRs for which there are no ligands) rely on CD94/NKG2A as their major-histocompatibility-complex-specific inhibitory receptor. The KIR ligand mismatch model predicts NK cell alloreactivity when NK cells express KIRs with their ligands in the donor but missing in the patient. In contrast, the missing KIR ligand model predicts NK cell alloreactivity when NK cells express KIRs for which there are no ligands in the patient, irrespective of the presence of these ligand in the donor.