Decreased expression of DNAM‐1 on NK cells from acute myeloid leukemia patients

Abstract

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...

Defective NK Cells in Acute Myeloid Leukemia Patients at Diagnosis Are Associated with Blast Transcriptional Signatures of Immune Evasion

“…Previous studies described NK cell defects in AML patients including a decreased expression of NKp30 and NKp46 (10,47) and DNAM-1 (48). Such downregulation may be related to the engagement of the NK cell activating receptors by their ligands on the leukemic blasts (48,49). However, in vivo NK cell's defects are only partially explained by such mechanisms.…”

“…AML cells can trigger NK cell cytotoxicity and IFN-g release, as demonstrated in adoptive therapy approaches involving allogeneic NK cells (2,4). Previous studies described NK cell defects in AML patients including a decreased expression of NKp30 and NKp46 (10,47) and DNAM-1 (48). Such downregulation may be related to the engagement of the NK cell activating receptors by their ligands on the leukemic blasts (48,49).…”

Loss of STAT3 in murine NK cells enhances NK cell–dependent tumor surveillance

“…[29][30][31] We used the well-established Bcr/Abl leukemia model to test the effect of deleting STAT3. We subcutaneously injected v-abl Finally we injected newborn mice with a replication-incompetent ecotropic retrovirus encoding for v-abl.…”

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

“…28 DNAM-1 is known to be involved in NK cell adhesion, activation and tumor immune surveillance, and is often downregulated on immune cells from AML patients. 12 The observed poor NK cell conjugation and killing of AML cells suggested that the DNAM-1-CD112/155 receptor-ligand axis might not be functioning optimally. To investigate this, we initially screened the AML cell lines for expression of the DNAM-1 ligands, CD112 and CD155.…”

“…9 Examples of such immune evasion tactics include a dull NCR profile through downregulation of NKp30 and NKp44, 10 loss of NKG2D ligand expression (MICA/B, ULBPs) 11 and perturbation of the DNAM-1-CD112/CD155 axis by inducing downregulation of DNAM-1 expression on NK cells. 12 Therefore, compounds that can increase the activity of NK cells toward AML are of considerable therapeutic interest. Indeed, cytokines, antibodies and drugs can enhance NK cell activity through a variety of mechanisms, including upregulation of NK-cell-activating receptors and their corresponding ligands on AML cells.…”