Activated natural killer cells from patients with acute myeloid leukemia are cytotoxic against autologous leukemic blasts in NOD/SCID mice

Abstract

Natural killer (NK) cells are implicated in the surveillance of hematological malignancies. They participate in the immune response against residual acute myeloid leukemia (AML) after hematopoietic stem cell transplantation with partial HLA class I disparity. However, the role of NK cells in autologous leukemia-specific immunity remains poorly understood. We studied the function of NK cells in AML patients at diagnosis. Following isolation, CD56+CD3- cells exhibited a high proliferative potential in vitro in response to interleukin (IL)-2. The polyclonal population of activated AML-NK cells expressed normal levels of the activating receptor NKG2D and the major natural cytotoxicity receptor NKp46. AML-NK cells were highly effective with respect to interferon-gamma production, cytotoxicity against HLA class I-deficient K562 erythroleukemia cells in vitro and retardation of tumor growth in vivo in K562-bearing NOD/SCID mice. Importantly, when AML blasts were injected into NOD/SCID mice, a single dose of adoptively transferred autologous AML-NK cells significantly reduced the AML load by 8-77%. Recognition of AML blasts may be related to the observed upregulation of ligands for NKG2D and natural cytotoxicity receptors in vivo. We conclude that AML patient-derived NK cells are fully functional, in support of exploring the benefit of AML immunotherapy with IL-2-stimulated autologous NK cells.

Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome

“…32 In parallel, studies have decoded the crucial receptor-ligand interactions for recognition of more complex primary tumor targets including freshly isolated leukemic blasts. 41,42 NK-cell recognition of myeloma seems to depend primarily on DNAM-1, whereas recognition of AML primarily relies on NKG2D. 21 Similarly, a role for NKG2D has been suggested in NK cellmediated killing of the MDS clone.…”

Natural killer cell immune escape in acute myeloid leukemia

“…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.…”

NK cell receptors and their ligands in leukemia

“…Downregulation of the activating receptors on NK cells from AML patients may explain the observed reduced NK killing of autologous AML cells and the HLA class I-deficient K562 cell line. 6,7,9,56 Unfortunately, the expression of the activating DNAM-1 receptor on NK cells from AML patients has not yet been analyzed. It has also been suggested that direct cell contact between leukemic blasts and NK cells rather than secretion of TGF-b 1 may induce downregulation of the NCRs.…”

“…53,55 An upregulation of NKG2D ligands on leukemic cells by growth factors could enhance NK cellmediated killing. 7 An overview of the expression of different NK activating ligands on AML cells is given in Table 3. Furthermore, Costello et al 6,56 demonstrated that the majority of NK cells in AML patients display a low NCR surface density correlating with their weak cytolytic activity against autologous leukemic cells.…”

“…1,2 The number or activity of autologous NK cells against leukemic cells is frequently reduced and abnormalities at the level of receptors and/or ligands determining NK cell function may be responsible for the resistance of leukemic cells to NK cells. [3][4][5][6][7][8][9] There is also still a high occurrence of leukemic relapse after high dose chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT), suggesting that leukemic cells can escape from the immune system. A variety of studies are now ongoing to unravel the mechanisms of NK cell killing of leukemic targets and to explain how leukemia can escape from the innate immune surveillance.…”