This study tested the hypothesis that the expression of CD112 and CD155 (DNAM-1 ligands) on leukemic blasts induces a decreased expression of the activating receptor DNAM-1 on natural killer (NK) cells from acute myeloid leukemia (AML) patients. DNAM-1 is a co-receptor involved in the activation of NK cell cytotoxicity after its interaction with its ligands CD112 and CD155 on target cells. Here we study the expression of DNAM-1 on NK cells and DNAM-1 ligands on blasts from AML patients stratified by age. The results demonstrate that NK cells from AML patients younger than 65 years have a reduced expression of DNAM-1 compared with age-matched controls. The analysis of DNAM-1 ligands showed a high expression of CD112 and CD155 on leukemic blasts. An inverse correlation between CD112 expression on leukemic blasts and DNAM-1 expression on NK cells was found. Furthermore, downregulation of DNAM-1 was induced on healthy donors' NK cells after in vitro culture with leukemic blasts expressing DNAM-1 ligands. In conclusion, these results support the hypothesis that receptor-ligand crosslinking downregulates DNAM-1 expression on NK cells from patients o65 years of age. Considering the relevance of DNAM-1 in NK recognition and killing of leukemic cells, the reduced expression of this receptor on NK cells from AML patients can represent an additional mechanism of tumor escape. Keywords: acute myeloid leukemia; aging; cancer; DNAM-1; natural killer cells Natural killer (NK) cells are lymphocytes of the innate immune system specialized in the recognition and lysis of tumors and virus-infected cells. 1 NK cell function is dictated by the balance of signals from inhibitory and activating receptors on the surface of NK cells that recognize their ligands on target cells. [1][2][3][4][5][6] Activating signals are mediated by a wide array of receptors, including, among others, NKG2D, natural cytotoxicity receptors, which include NKp30, NKp46 and NKp44 and DNAX accessory molecule-1 (DNAM-1, also known as CD226). The DNAM-1 receptor is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. In humans, DNAM-1 is expressed on NK, T cells, monocytes, a subset of B cells 7 and platelets. 8 Stimulation of DNAM-1 by its interaction with its ligands CD155 (poliovirus receptor) and CD112 (Nectin-2) leads to NK-cell activation and target cell lysis. 9-12 DNAM-1 ligands can be expressed on different types of tumors, including leukemia, myeloma, ovarian carcinoma and melanoma. [13][14][15][16] Thus, previous data support the involvement of DNAM-1 in the lysis of leukemic blasts mediated by NK cells. 13 Accumulating evidences strongly support a role for NK cells in the anti-tumor response against hematological malignancies. 5,17-19 Acute myeloid leukemia (AML) is generally considered a disease of older adults as more than half of AML patients are over the age 65 years at diagnosis. In addition, age has a profound impact in the prognosis of AML patients, as refractoriness of the disease and frailty of this population contributes...

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Natural killer (NK) cells are a key component of innate immunity involved not only in the elimination of virus-infected or tumor cells but also in the regulation of the immune response by producing cytokines and chemokines that can activate other cellular components of innate and adaptive immunity. NK cell subsets are differentially affected by aging. Whereas CD56^bright cells are decreased in healthy elderly individuals, the CD56^dim subset is expanded. The expression of CD57, a marker of highly differentiated NK cells, is increased in the elderly; this supports the notion that a remodeling process of NK cell subsets occurs in aging with a gradual decrease in more immature CD56^bright NK cells and an increase in highly differentiated CD56^dim CD57+ NK cells. This NK cell redistribution can explain many of the phenotypic and functional changes in NK cells associated with healthy aging such as decreased proliferation and the maintenance of CD16-dependent cytotoxicity.

Knowledge of the interactions between MHC-unrestricted cytotoxic effector cells and solid tumour cells is essential for introducing more effective NK cell-based immunotherapy protocols into clinical practise. Here, to begin to obtain an overview of the possible universe of molecules that could be involved in the interactions between immune effector cells and melanoma, we analyse the surface expression of adhesion and costimulatory molecules and of ligands for NK-activating receptors on a large panel of cell lines from the "European Searchable Tumour Cell Line and Data Bank" (ESTDAB, http://www.ebi.ac.uk/ipd/estdab/ ) and discuss their potential role in the immune response against this tumour. We show that most melanoma cell lines express not only adhesion molecules that are likely to favour their interaction with cells of the immune system, but also their interaction with endothelial cells potentially increasing their invasiveness and metastatic capacity. A high percentage of melanoma cell lines also express ligands for the NK-activating receptor NKG2D; whereas, the majority express MICA/B molecules, ULBP expression, however, was rarely found. In addition to these molecules, we also found that CD155 (poliovirus receptor, PVR) is expressed by the majority of melanoma cell lines, whereas CD112 (Nectin-2) expression was rare. These molecules are DNAM-1 ligands, a costimulatory molecule involved in NK cell-mediated cytotoxicity and cytokine production that also mediates costimulatory signals for triggering naïve T cell differentiation. The phenotypical characterisation of adhesion molecules and ligands for receptors involved in cell cytotoxicity on a large series of melanoma cell lines will contribute to the identification of markers useful for the development of new immunotherapy strategies.

Human adipose-derived stem cells (hASCs) have been successfully used in treating numerous diseases. However, several aspects need to be considered, particularly in the context of allogeneic cell therapy. To better understand hASCs-host interactions, we studied the phenotype of hASCs and their modulatory effect on natural killer (NK) cells by using bone marrow-mesenchymal stem cells (hBM-MSCs) as a reference. The hASCs displayed a lower susceptibility to NK cell-mediated lysis and a lower expression of ligands for DNAM-1 when compared with hBM-MSCs. Moreover, here we demonstrated that hASCs and hBM-MSCs can modulate NK cells through the action of soluble factors such as indoleamine 2,3-dioxygenase. Altogether, these results suggest that for an adoptive cell therapy based on the transfer of allogeneic hASCs, the NK-hASCs crosstalk will not result in an immediate recognition of the transferred cells. Thus, hASCs may remain in the tissue long enough to balance the immune response before being cleared.