Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

Abstract

Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56(bright) cells and an accumulation of highly differentiated CD56(dim) NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients.

Keywords: AML; Ageing; DNAM-1; NK cells; NKp30; NKp46.

Fig. 1

NK cell-activating receptors and their ligands in AML. Schematic representation of a the expression of activating receptors on NK cells from AML patients (AML–NK) and b their ligands on leukaemic cells

Fig. 2

IL-15 modulates the surface expression of activating receptors in NK cells and restores their functionality. A representative example from an elderly AML patient (82 years) showing the effect of in vitro incubation of NK cells with IL-15 (100 ng/ml): a expression of activating receptors on NK cells. Black lines represent expression levels of activating receptors in resting NK cells from an AML patient (AML-NK) at diagnosis, and grey-filled histograms indicate expression levels of activating receptors in AML-NK cells after incubation with IL-15. b Analysis of AML-NK cell degranulation against K562 cell line before and after preincubation of NK cells with IL-15

Fig. 3

Schematic representation of the effect of ageing and AML on NK cell phenotype and function and possible NK-based immunotherapy strategies. Ageing is associated with a decrease in the production of new immature CD56^bright NK cells from bone marrow common progenitors. CMV chronic infection is associated with an expansion of a memory-like long-lived NK cell subset characterized by the expression of the activating receptor CD94/NKG2C and CD57. Ageing and AML are associated with a decreased expression of NCRs and DNAM-1 that contributes to low cytotoxic capacity of NK cells. In elderly AML patients, age-associated changes on NK cells limit their capacity to eliminate leukaemic blasts. Interventions to improve NK cell function include cytokine-induced recovery of activating receptors and adoptive transfer of allogeneic NK cells selected on the basis of HLA/KIR mismatch. Novel strategies propose the use of NK cells expressing chimeric activating receptors (CAR) and the use of bi- or trispecific antibodies aimed to redirect NK cell-mediated lysis (BiKE and TriKE)