Genetic and Molecular Basis of Heterogeneous NK Cell Responses against Acute Leukemia

Abstract

Natural killer (NK) cells are key cytotoxic effectors against malignant cells. Polygenic and polymorphic Killer cell Immunoglobulin-like Receptor (KIR) and HLA genes participate in the structural and functional formation of the NK cell repertoire. In this study, we extensively investigated the anti-leukemic potential of NK cell subsets, taking into account these genetic parameters and cytomegalovirus (CMV) status. Hierarchical clustering analysis of NK cell subsets based on NKG2A, KIR, CD57 and NKG2C markers from 68 blood donors identified donor clusters characterized by a specific phenotypic NK cell repertoire linked to a particular immunogenetic KIR and HLA profile and CMV status. On the functional side, acute lymphoblastic leukemia (ALL) was better recognized by NK cells than acute myeloid leukemia (AML). However, a broad inter-individual disparity of NK cell responses exists against the same leukemic target, highlighting bad and good NK responders. The most effective NK cell subsets against different ALLs expressed NKG2A and represented the most frequent subset in the NK cell repertoire. In contrast, minority CD57+ or/and KIR+ NK cell subsets were more efficient against AML. Overall, our data may help to optimize the selection of hematopoietic stem cell donors on the basis of immunogenetic KIR/HLA for ALL patients and identify the best NK cell candidates in immunotherapy for AML.

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

“…Several studies reported that ALL blasts are not effectively killed by NK cells in vitro [ 115 , 116 , 117 , 118 ]. Although the reasons are not yet precisely understood, it is known that developing leukemia modifies NK cells’ education and maturation.…”

“…The molecular basis for the NK cells’ alloreactivity is the recognition of specific ligands for NK cell activating receptors and lack of recognition by the inhibitory receptors (“missing-self” reactivity) [ 64 ]. Research from the last decade provides information how HLA and KIR genotypes of the donors shape NK cell repertoire and alloreactivity of NK cells [ 117 ]. Pende et al presented that the activating receptor KIR2DS1, which recognizes HLA-C2 alleles on ALL cells, plays a major role in the lysis of leukemia cells by donor NK cells [ 130 ].…”

Paving the Way Towards Universal Chimeric Antigen Receptor Therapy in Cancer Treatment: Current Landscape and Progress

“…More importantly, tumor cells expressing KIRs ligands may inhibit the functions of some NK cell subsets via inhibitory KIRs. Additionally, it was observed that there was a broad inter-individual disparity in NK cell response against the same target as reported by Makanga et al (64). Therefore, in order to guide the selection of suitable NK subtypes from different donors, it is necessary to have a deeper understanding of the relationship between NK receptors and tumors.…”

Decreased iKIR-HLA C Pair Confers Worse Clinical Outcomes for Patients With Myeloid Disease Receiving Antithymocyte Globulin-Based Haploidentical Hematopoietic Stem Cell Transplantation

“…Makanga et al. demonstrated that CD57 + and KIR + NK cells from healthy individuals exhibited the highest degree of cytotoxicity against AML blasts, while ALL targets were less susceptible to KIR + NK subsets compared with NKG2A + NK subsets ( 36 ). On the basis of previous studies, we hypothesize that KIR may have a minor impact on the elimination of lymphoblastic leukemias, and patients with myeloid disease are more likely to benefit from well KIR-educated NK cells.…”