Cytomegalovirus: an unlikely ally in the fight against blood cancers?

Summary Cytomegalovirus (CMV) infection is a potentially fatal complication in patients receiving haematopoietic stem cell transplantation (HSCT), but recent evidence indicates that CMV has strong anti‐leukaemia effects due in part to shifts in the composition of natural killer (NK) cell subsets. NK cells are the primary mediators of the anti‐leukaemia effect of allogeneic HSCT, and infusion of allogeneic NK cells has shown promise as a means of inducing remission and preventing relapse of several different haematological malignancies. The effectiveness of these treatments is limited, however, when tumours express human leucocyte antigen (HLA)‐E, a ligand for the inhibitory receptor NKG2A, which is expressed by the vast majority of post‐transplant reconstituted and ex‐vivo expanded NK cells. It is possible to enhance NK cell cytotoxicity against HLA‐E pos malignancies by increasing the proportion of NK cells expressing NKG2C (the activating receptor for HLA‐E) and lacking the corresponding inhibitory receptor NKG2A. The proportion of NKG2C pos /NKG2A neg NK cells is typically low in healthy adults, but it can be increased by CMV infection or ex‐vivo expansion of NK cells using HLA‐E‐transfected feeder cells and interleukin (IL)‐15. In this review, we will discuss the role of CMV‐driven NKG2C pos /NKG2A neg NK cell expansion on anti‐tumour cytotoxicity and disease progression in the context of haematological malignancies, and explore the possibility of harnessing NKG2C pos /NKG2A neg NK cells for cancer immunotherapy.