NK cells and multiple myeloma-associated endothelial cells: molecular interactions and influence of IL-27

Abstract

Angiogenesis represents a hallmark of tumor progression in Multiple Myeloma (MM), a still incurable malignancy. Here we analyzed the activity of cytokine-stimulated NK cells against tumor-associated endothelial cells isolated from bone marrow aspirates of MM patients with active disease (MMECs). We show that NK cells activated with optimal doses of IL-15 killed MMECs thanks to the concerted action of multiple activating receptors. In particular, according to the high expression of PVR and Nectin-2 on MMECs, DNAM-1 actively participated in target recognition. Interestingly, in MMECs the surface density of PVR was significantly higher than that detected in endothelium from patients with MM in complete remission or with monoclonal gammopathy of undetermined significance (MGUS). Importantly, IL-27, which unlike IL-15 does not display pro-angiogenic properties, maintained or increased the NK cell functions induced by suboptimal concentrations of IL-15. NK cell properties included killing of MMECs, IFN-γ production as well as a peculiar increase of NKp46 expression on NK cell surface. Finally, IL-27 showed a striking capability of up-regulating the expression of PD-L2 and HLA-I on tumor endothelium, whereas it did not modify that of PD-L1 and HLA-II.Our results suggest that cytokine-activated endogenous or adoptively transferred NK cells might support conventional therapies improving the outcome of MM patients.

Novel Immunoregulatory Functions of IL-18, an Accomplice of TGF-β1

“…In particular, IL-18 potentiated the TGF-β1-mediated downregulation of NKp30, with a virtual total loss of its capability to trigger the NK cells cytolytic activity. This might lead to a decreased ability of NK cells to kill targets that express the specific ligand(s), which include tumors of different histotype [27] and tumor-associated endothelial cells [28]. Notably, the NKp30 receptor is also involved, together with DNAM-1, in NK/DC interactions that lead to reciprocal cell activation [29,30,31,32].…”

The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment

“…The endothelial reaction in hypoxia contributes to selection, differently than in normoxia, of the immune cells’ entry inside the tumor. We could show that although the direct interaction of NK cells with endothelial cells [ 22 ] is increased upon NK cell activation by IL-2 [ 23 ] as well as IL-15 and IL-27 [ 24 ], hypoxia modulates the recognitions in an opposite manner by reducing NK cell adhesion to the tumor endothelium in the mammary carcinoma [ 10 ], similarly to the case of multiple myeloma-associated endothelial cells ( Fig. 1 ) [ 24 ].…”

Microvesicles produced by natural killer cells of the NK-92 cell line affect the phenotype and functions of endothelial cells of the EA.Hy926 cell line

“…Conflicting findings on the role of NK cells in angiogenesis have been seen in various model experiments conducted in vitro. There is evidence that they stimulate vessel EC migration and formation [25,29], and that they inhibit angiogenesis processes [16,21]. It has been established that IL-15 increases production of VEGF and PlGF by NK cells [26,40].…”