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

Alessandra Dondero,Cristina Bottino,Maria Antonia Frassanito,Alessandro Moretta,Roberta Castriconi,Daniel Olive,Annunziata De Luisi,Claudia Cantoni,Francesca Bellora,Silvia Gaggero,Angelo Vacca,Beatrice Casu

doi:10.18632/oncotarget.17070

Alessandra Dondero, Cristina Bottino + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.17070

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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.

Highlights

In the last decades important advancements in the treatment of different malignances have led to significant improvement in patients’ survival
MM patients with active disease (MMECs) were analyzed for the susceptibility to lysis mediated by peripheral blood mononuclear cells (PBMCs) of healthy donors activated with optimal doses of rIL-15 (20 ng/ml) (Figure 1A)
Assuming a predominant role of NK lymphocytes in the killing of MMECs by rIL-15 activated PBMCs, we analyzed the susceptibility of MMECs to lysis mediated by highly purified activated NK cells (Figure 1B)

Summary

Introduction

In the last decades important advancements in the treatment of different malignances have led to significant improvement in patients’ survival. A variety of therapies are currently available including those targeting specific pathways involved in the growth and survival of cancer cells or tumor-associated stromal cells such as endothelial cells. A pro-tumoral crosstalk between cancer and endothelial cells occurs and is essential for tumor growth. In multiple myeloma (MM), an incurable malignancy of monoclonal plasma cells [1], angiogenesis represents a hallmark of tumor progression and antiVEGF drugs, alone or in combination with other agents, are currently used. Available therapeutic approaches resulted in limited benefits and in a short-lasting tumor regression. Many efforts have been made to evaluate additional therapeutic protocols aimed at obtaining a more durable tumor control in different malignances including MM. New strategies consist of immunotherapeutic approaches including the strengthening of the function of endogenous Natural www.impactjournals.com/oncotarget

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