NK Cells Mediate a Crucial Graft-versus-Leukemia Effect in Haploidentical-HSCT to Cure High-Risk Acute Leukemia

Natural killer (NK) cells are involved in innate defenses against viruses and tumors. Their function is finely tuned by activating and inhibitory receptors. Among the latter, killer immunoglobulin-like receptors and CD94/NKG2A recognize human leukocyte antigen (HLA) Class I molecules, allowing NK cells to discriminate between normal and aberrant cells, as well as to recognize allogeneic cells, because of their ability to sense HLA polymorphisms. This latter phenomenon plays a key role in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for high-risk acute leukemia patients transplanted from an NK-alloreactive donor. Different haplo-HSCT settings have been developed, either T depleted or T replete – the latter requiring graft-versus-host disease prophylaxis. A novel graft manipulation, based on depletion of αβ T cells and B cells, allows infusion of fully mature, including alloreactive, NK cells. The excellent patient clinical outcome underscores the importance of these innate cells in cancer therapy. T cell-depleted haplo-identical HSCT represents a novel approach based on grafts depleted of αβT and B cells. This method allows the prompt availability of potent effector cells (i.e., NK and γδT cells), capable of preventing leukemia relapse and controlling infections. KIR-mediated recognition of epitopes shared by HLA Class I alleles is the basis for the NK alloreactivity, which is crucial for the graft-versus-leukemia effect and prevention of graft-versus-host disease in T cell-depleted haplo-HSCT. CMV infection/reactivation drives the expansion of adaptive NK cell subsets displaying specialized effector function and long-term persistence. These cells may be harnessed as immunotherapeutic tools. NK cells may represent a suitable platform for novel therapeutic approaches, such as CAR-engineered NK cells. In addition, the use of monoclonal antibodies against inhibitory checkpoints may unleash antitumor NK cell function.