NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities

Abstract

IntroductionImproved outcome of acute myeloid leukemia (AML) after stemcell transplantation across the human leukocyte antigen (HLA) class I barrier highlighted a potential of natural killer (NK) cells in recognition and elimination of residual malignant cells by the graft-versus-leukemia (GVL) effect in the absence of graft-versushost disease (GVHD). 1,2 NK cells develop rapidly from transplanted progenitor cells but display numerous phenotypic abnormalities and a functional immaturity, which may limit their effectiveness in tumor rejection in vivo. 3,4 Adoptive transfer of mature NK cells in the early posttransplantation period is therefore a rational approach aimed at providing the patient with the benefit of competent cytotoxic effectors. 5 NK cells are innate immunity CD56 ϩ CD3 Ϫ lymphocytes, the function of which is regulated by the integration of signals delivered from multiple inhibitory and activating receptors. 6 The killer immunoglobulin-like receptors (KIRs), which are clonally distributed in the NK-cell repertoire, recognize allelic groups of HLA class I molecules on target cells and are dominant determinants of NK-cell function. 7 NK cytotoxicity is inhibited on recognition of "self" HLA class I molecules, whereas absence or loss of HLA class I can render cells susceptible to NK-mediated lysis. In the transplant setting from haploidentical stem-cell donor, alloreactivity of NK cells is provided by the KIR-HLA class I mismatch. 8 In addition to sensing the missing self HLA class I molecules, NK cells need to be stimulated through engagement of activating NK receptors by specific cell-surface ligands expressed by target cells. 9,10 NKG2D is one of the best characterized receptors required for NK-mediated tumor immunosurveillance. 11 In mice, NKG2D function can protect the host from tumor initiation and also eradicate existing tumors expressing the H60 and Rae-1 ligands. 12,13 The human NKG2D ligands (NKG2D-L) include 2 families of proteins belonging to major histocompatibility complex class I (MIC)-related molecules, and UL-16 binding proteins (ULBP). 14,15 In epithelial tissue, the surface expression of NKG2D-L is up-regulated in response to cellular stress, including heat shock, DNA damage, and stalled DNA replication, which are common in human cancer. 16,17 A notion that NKG2D-L play a key role as tumor-associated ligands rendering cells susceptible to NK-mediated lysis, has encouraged pharmacologic approaches to achieve the NKG2D-L induction. 18,19 Understanding the molecular interactions regulating the NK function has uncovered numerous escape mechanisms preventing recognition of leukemic blasts by NK cells. Unlike in solid tumors, which frequently down-regulate HLA class I molecules, malignant leukemic cells carry high levels of HLA class I having a protective effect. 20 NKG2D-L are absent or expressed at low levels in the majority of patients with acute leukemia, 21-23 thereby preventing efficient activating interactions. An additional route of tumor The online version of this article contain...

Natural killer cell immune escape in acute myeloid leukemia

“…For more than a decade, however, an impaired NK cell cytotoxic capacity in AML patients is acknowledged. [17][18][19][20][21][22] NK-cellmediated killing of a target cell depends on the balance between Impaired NK cell-mediated cytotoxicity AML cell shedding of NKG2D-L MIC and ULBP molecules 43,44 Reduced receptor expression and impaired NK cell-mediated cytotoxicity AML cell GITRL expression 45 Surface and soluble GITRL expression (surface expression is related to monocytic differentiation)…”

“…27,28,42,43 Furthermore, AML cells can shed ligands for NKG2D, as demonstrated by the increased serum levels of MHC class I chain-related genes A and B (MICA/B) in AML patients compared with healthy controls. 43,44 These soluble ligands may provide a chronic systemic stimulus to NK cells resulting in reduced receptor expression and impaired NK cell-mediated cytotoxicity (Table 1). 43 Strongly supportive of this hypothesis is the recent finding that DNAM-1 expression can be downregulated on NK cells from healthy donors through in vitro culture with leukemic blasts expressing DNAM-1 ligands.…”

“…97 In analogy with the lowered activating receptor expression, surface expression of NKG2D ligands (MIC and ULBP molecules) is low or absent on AML blasts and is related to impaired NK cell-mediated cytotoxicity (Table 1). 28,[42][43][44]98 In addition, secretion of soluble NKG2D ligands in AML contributes to evasion of NK cell surveillance (Table 1). 43,44 In this regard, an attractive immunotherapy would be to upregulate these ligands on AML cells to enhance their susceptibility to NK cell recognition and restore their sensitivity to NK cell killing.…”

“…83,99 All-transretinoic acid and the histone deacetylase inhibitor sodium valproate were repeatedly shown to induce NKG2D ligand expression in certain types of tumors, including AML, 44,100,101 leading to an improved sensitivity to NK cell-mediated killing. Promotors of myeloid cell differentiation trichostatin A and vitamin D3 were also shown to upregulate NKG2D ligands on AML cells.…”

Exosomes from Murine-derived GL26 Cells Promote Glioblastoma Tumor Growth by Reducing Number and Function of CD8+T Cells

“…Many mechanisms of tumor escape from immune systems have been reported previously: absent or low expression of molecules on tumor cells involved in tumor target cell recognition (Diermayr et al, 2008); absence of co-stimulation leading to tolerization of T cells (den et al, 2004); soluble factors secreted by tumor cells inhibiting T cell response; and regulatory T cells, myeloid suppressor cells, and stromal cells may impair immune-cell responses to tumors (Johann et al, 2010;Bacić et al, 2011;Zamarron et al, 2011). Furthermore, tumors can release soluble molecules such as HLA-I (sHLA-I).…”