Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:35088-35102. https://doi.org/10.18632/oncotarget.17070

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Abstract

Alessandra Dondero1, Beatrice Casu1, Francesca Bellora1, Angelo Vacca2, Annunziata De Luisi2, Maria Antonia Frassanito2, Claudia Cantoni1,3,4, Silvia Gaggero1, Daniel Olive5, Alessandro Moretta1, Cristina Bottino1,3,*, Roberta Castriconi1,4,*

1Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy

2Department of Biomedical Sciences and Human Oncology, University of Bari, 70124 Bari, Italy

3Istituto Giannina Gaslini, 16147 Genova, Italy

4Center of Excellence for Biomedical Research (CEBR), University of Genova, 16132 Genova, Italy

5U1068, CRCM, Immunity and Cancer, INSERM, 13009 Marseille, France

*Co-seniorship

Correspondence to:

Cristina Bottino, email: Cristina.Bottino@unige.it

Keywords: multiple myeloma, endothelial cells, NK cells, IL-27, PD-Ls

Received: June 30, 2016     Accepted: March 27, 2017     Published: April 12, 2017

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.


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PII: 17070