Universität zu Köln

Schlecker, Eva, Fiegler, Nathalie, Arnold, Annette, Altevogt, Peter, Rose-John, Stefan ORCID: 0000-0002-7519-3279, Moldenhauer, Gerhard, Sucker, Antje, Paschen, Annette, von Strandmann, Elke Pogge, Textor, Sonja and Cerwenka, Adelheid (2014). Metalloprotease-Mediated Tumor Cell Shedding of B7-H6, the Ligand of the Natural Killer Cell-Activating Receptor NKp30. Cancer Res., 74 (13). S. 3429 - 3441. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

Natural killer (NK) cells are potent immune effector cells capable of mediating antitumor responses. Thus, during immunoediting, tumor cell populations evolve strategies to escape NK-cell-mediated recognition. In this study, we report a novel mechanism of immune escape involving tumor cell shedding of B7-H6, a ligand for the activating receptor NKp30 that mediates NK-cell binding and NK-cell-mediated killing. Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases a disintegrin and metalloproteases (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells. Notably, we documented elevated levels of soluble B7-H6 levels in blood sera obtained from a subset of patients with malignant melanoma, compared with healthy control individuals, along with evidence of elevated B7-H6 expression in melanoma specimens in situ. Taken together, our results illustrated a novel mechanism of immune escape in which tumor cells impede NK-mediated recognition by metalloprotease-mediated shedding of B7-H6. One implication of our findings is that therapeutic inhibition of specific metalloproteases may help support NK-cell-based cancer therapy. (C) 2014 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schlecker, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Fiegler, Nathalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Arnold, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Altevogt, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Rose-John, Stefan UNSPECIFIED orcid.org/0000-0002-7519-3279 UNSPECIFIED Moldenhauer, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Sucker, Antje UNSPECIFIED UNSPECIFIED UNSPECIFIED Paschen, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED von Strandmann, Elke Pogge UNSPECIFIED UNSPECIFIED UNSPECIFIED Textor, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Cerwenka, Adelheid UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-435203
DOI:	10.1158/0008-5472.CAN-13-3017
Journal or Publication Title:	Cancer Res.
Volume:	74
Number:	13
Page Range:	S. 3429 - 3441
Date:	2014
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHAIN-RELATED MOLECULE; NKG2D LIGANDS; CUTTING EDGE; DOWN-REGULATION; MYELOID CELLS; NK CELLS; MALIGNANT DISEASES; ANTITUMOR-ACTIVITY; BREAST-CANCER; UP-REGULATION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43520