Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction

Abstract

Natural killer (NK) cells play an important

Natural killer cell immune escape in acute myeloid leukemia

“…The majority of AML patients have a downregulated NK cell surface expression of the activating natural cytotoxicity receptors (NCRs; that is, NKp30, NKp44 and NKp46). [24][25][26] Recently, also the expression of DNAX accessory molecule-1 (DNAM-1) was shown to be reduced on NK cells from AML patients younger than 65 years compared with age-matched controls. 27 Together with the activating NK cell receptor NKG2D, these are the main receptors involved in NK cell-mediated recognition and killing of leukemic target cells.…”

“…28 Importantly, NCR downregulation (NCR dull ) on NK cells was found to be associated with poor prognosis for AML patients, as NCR dull AML patients showed significantly lower 5-year survival rates than their NCR bright counterparts. 25 Besides the activating receptor status, the inhibitory receptor phenotype also has a role in the escape of AML from NK cells. KIRs are a major NK cell receptor family with important inhibitory potential.…”

“…Fortunately, it has also been confirmed that NK cells derived from AML patients post therapy can be fully functional and that the altered NK cell phenotype is reversible. 25,26,41,76,79 Moreover, CD56 bright NK cells are strong cytokine-secreting cells, vital for the initiation of adaptive immunity and cell proliferation, hence attractive for the generation of sustained anti-leukemic immunity. 80 Altogether, this knowledge prompts further exploration of enforcing NK cells in AML patients that achieved complete remission.…”

Early evaluation of natural killer activity in post-transplant acute myeloid leukemia patients

“…25 Moreover, it has been shown that the down-regulation of NCRs is common in AML and that this phenomenon may lead to defective anti-leukemic response. 26,27 In this study, we ex-vivo explored the function of early reconstituted NK cells following non-haploidentical HSCT. We show for the first time that NK degranulation may fluctuate between day 30 (D30) and day 60 (D60), undergoing a significant down-regulation specific to AML patients at D60.…”

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

“…8 AML blasts can escape NK cell-mediated lytic activity through an extensive process of immune-editing, in which multiple NK cell activation receptors and their ligands are manipulated to inhibit NK cell function (conjugation, degranulation and tumor cell lysis), leading to the induction of NK cell tolerance. 9 Examples of such immune evasion tactics include a dull NCR profile through downregulation of NKp30 and NKp44, 10 loss of NKG2D ligand expression (MICA/B, ULBPs) 11 and perturbation of the DNAM-1-CD112/CD155 axis by inducing downregulation of DNAM-1 expression on NK cells. 12 Therefore, compounds that can increase the activity of NK cells toward AML are of considerable therapeutic interest.…”