Relevance of Polymorphic KIR and HLA Class I Genes in NK-Cell-Based Immunotherapies for Adult Leukemic Patients

Abstract

Since the mid-1990s, the biology and functions of natural killer (NK) cells have been deeply investigated in healthy individuals and in people with diseases. These effector cells play a particularly crucial role after allogeneic hematopoietic stem-cell transplantation (HSCT) through their graft-versus-leukemia (GvL) effect, which is mainly mediated through polymorphic killer-cell immunoglobulin-like receptors (KIRs) and their cognates, HLA class I ligands. In this review, we present how KIRs and HLA class I ligands modulate the structural formation and the functional education of NK cells. In particular, we decipher the current knowledge about the extent of KIR and HLA class I gene polymorphisms, as well as their expression, interaction, and functional impact on the KIR+ NK cell repertoire in a physiological context and in a leukemic context. In addition, we present the impact of NK cell alloreactivity on the outcomes of HSCT in adult patients with acute leukemia, as well as a description of genetic models of KIRs and NK cell reconstitution, with a focus on emergent T-cell-repleted haplo-identical HSCT using cyclosphosphamide post-grafting (haplo-PTCy). Then, we document how the immunogenetics of KIR/HLA and the immunobiology of NK cells could improve the relapse incidence after haplo-PTCy. Ultimately, we review the emerging NK-cell-based immunotherapies for leukemic patients in addition to HSCT.

Role of NK cells in cord blood transplantation and their enhancement by the missing ligand effect of the killer-immunoglobulin like receptor

“…KIR is one of the major receptors involved in regulating the activity and differentiation of NK cells ( Leung, 2011 ; Dubreuil et al, 2021 ) There are two major subtypes of KIR—stimulatory and inhibitory receptors. Some KIRs can recognize HLA class I as a ligand.…”

“…There is another well-tested model that considers the presence of the donor’s stimulatory KIR. The KIR gene cluster is located on chromosome 19 and its haplotypes are classified into two major groups ( Leung, 2011 ; Dubreuil et al, 2021 ). Haplotype group A have only one stimulatory KIR, KIR2DS4, in addition to the inhibitory KIRs, whereas group B have several other stimulatory KIRs.…”

Decision trees to evaluate the risk of developing multiple sclerosis

“…The main function of these receptors is to reduce the lymphocyte activation and attenuate the innate killing capacity of NK cells ( Hanson et al, 2022 ). NK cells express 15 unique KIR receptors that have different interactions with specific subtypes of HLA Class I molecules ( Dubreuil et al, 2021 ). The interaction KIR/HLA results in either activation or inhibitory signals ( Biassoni and Malnati, 2018 ).…”

NK cell subsets and dysfunction during viral infection: a new avenue for therapeutics?

“…The HLA gene family, whose constituents serve as ligands for many NK cell receptors encompasses more than 35,000 different MHC alleles, making it the most polymorphic region in the human genome ( 37 ). The implications of this diversity on NK cell signaling are made very apparent by the observation that various combinations of KIR receptors and HLA ligand have displayed differential functional activation ( 32 , 38 – 40 ), and have additionally been associated with infection outcome in human immunodeficiency virus (HIV) ( 41 , 42 ), hepatitis C virus (HCV) ( 43 ), SARS-CoV-2 ( 44 ), and ebola virus ( 45 ).…”