Abstract
Natural killer (NK) cells contribute to the first line of defense against viruses and to the control of tumor growth and metastasis spread. The discovery of HLA class I specific inhibitory receptors, primarily of killer Ig-like receptors (KIRs), and of activating receptors has been fundamental to unravel NK cell function and the molecular mechanisms of tumor cell killing. Stemmed from the seminal discoveries in early ‘90s, in which Alessandro Moretta was the major actor, an extraordinary amount of research on KIR specificity, genetics, polymorphism, and repertoire has followed. These basic notions on NK cells and their receptors have been successfully translated to clinical applications, primarily to the haploidentical hematopoietic stem cell transplantation to cure otherwise fatal leukemia in patients with no HLA compatible donors. The finding that NK cells may express the PD-1 inhibitory checkpoint, particularly in cancer patients, may allow understanding how anti-PD-1 therapy could function also in case of HLA class Ineg tumors, usually susceptible to NK-mediated killing. This, together with the synergy of therapeutic anti-checkpoint monoclonal antibodies, including those directed against NKG2A or KIRs, emerging in recent or ongoing studies, opened new solid perspectives in cancer therapy.
Highlights
The groundbreaking discoveries made by Alessandro Moretta left a very big footprint in Immunology, and, more generally, in Medicine [1, 2]
Since the beginning of his scientific career, Alessandro focused his research on two different issues that revealed to be fundamental for his future major accomplishments: on one side, the generation of monoclonal antibodies to functional surface molecules expressed by human T cells, and on the other side, the development of a highly efficient T cell cloning technique allowing clonal growth of virtually 100% T cells [4]
Based on the expression of inhibitory checkpoint ligands on tumor cells, three therapeutic approaches have been proposed: [1] HLA-Epos tumors lacking the expression of other ligands for inhibitory checkpoints or tumor antigens: blocking of NKG2A could unleash both natural killer (NK)- and Tcell-mediated antitumor responses in a murine model; [2] tumors expressing both HLA-E and PD-L1: by the combined blocking of NKG2A and PD-1/PD-L1 axis, enhancement of NK and T cell cytotoxicity and induction of T cell proliferation and establishment of T cell memory were detected; [3] tumors expressing HLA-E and specific tumor antigens (e.g., EGF-R): blockade of NKG2A increased the efficacy of anti-EGF-R by allowing a CD16-mediated efficient ADCC by mature, highly cytotoxic NK cells
Summary
The groundbreaking discoveries made by Alessandro Moretta left a very big footprint in Immunology, and, more generally, in Medicine [1, 2]. That “the music is over” [3] the Alessandro’s legacy will remain, witnessed by the many human lives saved thanks to his seminal studies and his continuous efforts to translate discoveries to the benefit of patients with leukemia or solid tumors
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