Strategies to activate NK cells to prevent relapse and induce remission following hematopoietic stem cell transplantation

Natural killer (NK) cells are lymphocytes of innate immunity that respond to virus infected and tumor cells. After allogeneic transplantation, NK cells are the first reconstituting lymphocytes, but are dysfunctional. Manipulating this first wave of lymphocytes could be instrumental in reducing the 40% relapse rate following transplantation with reduced-intensity conditioning. NK cells express numerous activating and inhibitory receptors. Some recognize classical or nonclassical HLA class I ligands, others recognize class I–like ligands or unrelated ligands. Dominant in the NK-cell transplant literature are killer cell immunoglobulin-like receptors (KIRs), encoded on chromosome 19q. Inhibitory KIR recognition of the cognate HLA class I ligand is responsible for NK-cell education, which makes them tolerant of healthy cells, but responsive to unhealthy cells having reduced expression of HLA class I. KIR A and KIR B are functionally distinctive KIR haplotype groups that differ in KIR gene content. Allogeneic transplant donors having a KIR B haplotype and lacking a recipient HLA-C epitope provide protection against relapse from acute myeloid leukemia. Cytomegalovirus infection stimulates and expands a distinctive NK-cell population that expresses the NKG2C receptor and exhibits enhanced effector functions. These adaptive NK cells display immune memory and methylation signatures like CD8 T cells. As potential therapy, NK cells, including adaptive NK cells, can be adoptively transferred with, or without, agents such as interleukin-15 that promote NK-cell survival. Strategies combining NK-cell infusions with CD16-binding antibodies or immune engagers could make NK cells antigen specific. Together with checkpoint inhibitors, these approaches have considerable potential as anticancer therapies.