Data Availability StatementThe material supporting the information of this review has been included within the article. for AML based on preclinical investigations and clinical trials. myeloid-derived suppressor cell, natural killer cell; regulatory T cell NK cell-mediated cytotoxicity is based on the notion of missing self-recognition and induced self-recognition [40]. During NK cell development, inhibitory KIR receptors encounter with MHC class I (MHC-I) ligands on their own hematopoietic cells, leading to the acquisition of functional competence and self-tolerance [41, 42]. Both the reduction/absence of MHC-I molecules and the upregulation/de novo expression of ligands for activating receptors on tumor cells can elicit NK cell immune response against non-self, through releasing cytotoxic granules, secreting cytokines and inducing death receptor-dependent apoptosis [36, 43]. Apart from the direct receptor-based acknowledgement between NK cells and tumor cells that potentiates the anti-tumor function of NK cells, they can kill tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC) as well, which is usually mediated by the IgG Fc receptor CD16 [44]. In addition, the activation of NK cells can be induced by other immune cells such as macrophages and dendritic cells (DCs) as well, either through direct cell-to-cell contacts or the release of cytokines such as IL-12, IL-15, IL-18 and IFN-/, promoting NK cell cytotoxicity and IFN- production [45, 46]. Dysfunction of NK cell-mediated anti-leukemia responses in patients with AML In AML, leukemia cells can escape from NK cell-mediated acknowledgement as a consequence of NK cell abnormalities, immunosuppressive properties of AML cells or interactions between NK cells and other immune cells in favor of immune escape (Fig.?1) [47]. Since the function of NK cells is usually tightly regulated by their sophisticated repertoire of inhibitory and activating receptors, imbalanced receptor expressions can lead to NK cell dysfunction. Studies evaluating the expression of these molecular receptors on NK cells showed the underexpression of activating receptors such as NKG2D, NCRs and DNAX accessory molecule-1 (DNAM-1) as well as overexpression of inhibitory receptors such as KIR2DL2/L3 and NKG2A in AML patients as compared with healthy controls [48C52]. Direct contact between AML cells and NK cells, high expression of CD200 on AML cells, soluble NKG2D ligands (NKG2DLs) in the sera and suppressive tumor microenvironment are factors that lead to defective receptor expression changes [49, 53, 54]. In addition to NK cell abnormalities, leukemia cells themselves displaying a defective expression of ligands for NK cell activating/inhibitory receptors give rise to the attenuation of NK cell-mediated anti-leukemia responses as well. For instance, the low expression of NKG2DLs [MHC class I chain-related proteins (MIC) and UL16-binding proteins (ULBP)], NCR ligands and DNAM-1 ligands (CD112 and CD155) on AML cells can render them resistant to NK cell killing [55, 56]. The deficient NKG2DL expression on AML cells may be caused by aberrant epigenetic mechanisms or the release of soluble forms from your cell surface by metalloproteinases [57, 58]. Whereas, upregulation of inhibitory immune checkpoint molecules programmed cell death ligand-1 (PD-L1) and PD-L2 is usually observed in AML blasts [59]. The tumor microenvironment, which possesses immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and tolerogenic DCs as well as immunosuppressive factors such as transforming growth factor (TGF)-, IL-10 and indoleamine 2,3 dioxygenase (IDO), is usually another major limitation to the effectiveness of NK cells in AML [60, 61]. It is worth noting that expressions of NK receptors and their cognate ligands on leukemic cells as well as the signals deriving from tumor microenvironment are deemed to impact clinical outcomes and relapse in AML Rabbit Polyclonal to MRPS24 patients [47]. These NK cell function-related adverse prognostic parameters including hypomaturation NK cell profile (CD56bright and KIR?/CD57?), increased NKG2A and decreased NCR on NK cells, increased CD200 and decreased ULBP1 on AML cells [49, 51, 53, 62C66]. Moreover, persistence of dysfunctional NK cells was found even in patients who accomplish first CR after rigorous chemotherapy [67]. Thus, the presence of dysfunctional NK cells in AML and their prognostic relevance provide the rationale for the use of NK cell-based immunotherapy to restore impaired NK cell cytotoxicity against AML. NK cell-based immunotherapy in AML Adoptive NK cell transfer The Liraglutide strategy of adoptive NK cell transfer was put forward based on beneficial effects of NK cell alloreactivity in the setting of allogeneic HCT (allo-HCT). NK cell alloreactivity is usually triggered by the mismatch between KIRs on donor NK cells and human leukocyte antigen (HLA) class I molecules on recipient cells, the effectiveness of which Liraglutide in leukemia was initially explained by Perugia group [68, 69]. Alloreactions mediated by donor NK cells can kill leukemia through graft-versus-leukemia (GvL) effect, promote engraftment through ablation of recipient T cells and protect against graft-versus-host disease (GvHD) through depleting recipient antigen-presenting cells and generating IL-10 [70, 71]. Liraglutide Transplantation from NK alloreactive donors is considered as a strong impartial factor predicting survival in allo-HCT recipients, especially from donors with more KIR B gene-content motifs.
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