Natural killer cell-triggering receptors in patients with acute leukaemia

Human natural killer (NK) cells are potent effectors involved in destruction of virus infected cells and tumours. Their cytolytic function is regulated by surface receptors that either inhibit or increase the NK-mediated cytotoxicity. Under physiological conditions, NK cells recognize major histocompatibility complex (MHC)-class I molecules through surface receptors delivering signals that inhibit NK cells function. Nonetheless, the "missing self hypothesis", i.e. the release of an inhibitory signal by the interaction between HLA I-specific inhibitory receptors and their ligands, is not sufficient to entirely explain the regulation of NK cytotoxicity. Activating and co-receptors also play a central role in NK cell activation. In the haematology field, several lines of evidence suggest that NKs participate to the anti-leukaemia immune response: (1) leukaemic cells have down-regulated HLA-class I molecule expression and putative allele loss, (2) several reports have indicated an inverse relationship between NK cell number or activity and prognosis in acute leukaemia, (3) NK-cell activity dependent immunodeficiency syndromes are associated with an increased frequency of lymphoid haematological malignancies, (4) recent data support a role for NK cells in the graft-versus-leukaemia effect observed in allogeneic bone marrow transplantation. All these data raise several questions. How NK cells kill leukaemic targets, and how can leukaemia escape from innate immunity surveillance? What are the therapeutic possibilities to manipulate NK receptor-ligand interaction in order to increase leukaemia cell destruction? The responses to these questions will contribute to immunotherapy advancements in leukaemia and more generally in cancer.