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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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