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.
Highlights
Natural killer (NK) cells are key cytotoxic effectors of innate immunity against malignant [1]and virally infected cells [2]
Given the diversity of NK cell responses based on the target cell nature, we aimed to characterize the phenotype of all target cell lines for the expression of NK receptor ligands known to be involved in the modulation of NK
Killer cell Immunoglobulin-like Receptor (KIR)+ NKG2A+ CD57− (4.99% versus 3.29, p = 0.0198) (Figure 4E). These results suggest a functional advantage of KIR+ NK cells against the KG1 cell line, even though they did not constitute the8best of 18 effectors
Summary
Virally infected cells [2]. They are able to sense the absence or the low expression of HLA. Cancers 2020, 12, 1927 class I molecules on cancer or virally infected cells via Killer cell Immunoglobulin-like Receptor (KIR) [3]. On the basis of their recognition of HLA class I, a strong interest in NK cells is focused on hematopoietic stem cell transplantation (HSCT) to optimize the graft-versus-leukemia (GvL) effect. In the context of acute leukemias, NK cell-mediated immunosurveillance requires the establishment of an immunological synapse between the NK cell and the leukemia target, involving a large number of interactions between inhibitory and activating NK receptors and their ligands expressed by leukemic cells. Inhibitory receptors mainly include KIR and NKG2A receptors, which are specific to HLA class. KIRs are clonally expressed on the surface of mature NK cells.
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