Universität zu Köln

Hansen, Hinrich P., Trad, Ahmad, Dams, Maria, Zigrino, Paola ORCID: 0000-0002-7470-0064, Moss, Marcia, Tator, Maximilian, Schoen, Gisela, Grenzi, Patricia C., Bachurski, Daniel ORCID: 0000-0001-9168-9680, Aquino, Bruno, Duerkop, Horst, Reiners, Katrin S., von Bergwelt-Baildon, Michael, Hallek, Michael, Groetzinger, Joachim, Engert, Andreas, Paes Leme, Adriana F. and von Strandmann, Elke Pogge (2016). CD30 on extracellular vesicles from malignant Hodgkin cells supports damaging of CD30 ligand-expressing bystander cells with Brentuximab-Vedotin, in vitro. Oncotarget, 7 (21). S. 30523 - 30536. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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Abstract

The goal of targeted immunotherapy in cancer is to damage both malignant and tumor-supporting cells of the microenvironment but spare unaffected tissue. The malignant cells in classical Hodgkin lymphoma (cHL) selectively express CD30. They release this receptor on extracellular vesicles (EVs) for the tumor-supporting communication with CD30 ligand (CD30L)-positive bystander cells. Here, we investigated how CD30-positive EVs influence the efficacy of the CD30 antibody drug conjugate (ADC) Brentuximab Vedotin (SGN-35). The malignant cells and the EVs expressed the active sheddase ADAM10. ADAM10 cleaved and released the CD30 ectodomain (sCD30), causing a gradual depletion of SGN-35 binding sites on EVs and creating a soluble competitor of the ADC therapy. In a 3D semi-solid tumor microenvironment model, the EVs were retained in the matrix whereas sCD30 penetrated readily into the surrounding culture medium. This resulted in a lowered ratio of EV-associated CD30 (CD30EV) to sCD30 in the surrounding medium in comparison to non-embedded cultures. A low percentage of CD30EV was also detected in the plasma of cHL patients, supporting the clinical relevance of the model. The adherence of CD30EV but not sCD30 to CD30-(/)CD30L(+) mast cells and eosinophils allowed the indirect binding of SGN-35. Moreover, SGN-35 damaged CD30-negative cells, provided they were loaded with CD30(+) EVs.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hansen, Hinrich P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Trad, Ahmad UNSPECIFIED UNSPECIFIED UNSPECIFIED Dams, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Zigrino, Paola UNSPECIFIED orcid.org/0000-0002-7470-0064 UNSPECIFIED Moss, Marcia UNSPECIFIED UNSPECIFIED UNSPECIFIED Tator, Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoen, Gisela UNSPECIFIED UNSPECIFIED UNSPECIFIED Grenzi, Patricia C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bachurski, Daniel UNSPECIFIED orcid.org/0000-0001-9168-9680 UNSPECIFIED Aquino, Bruno UNSPECIFIED UNSPECIFIED UNSPECIFIED Duerkop, Horst UNSPECIFIED UNSPECIFIED UNSPECIFIED Reiners, Katrin S. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Bergwelt-Baildon, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Groetzinger, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Engert, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Paes Leme, Adriana F. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Strandmann, Elke Pogge UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-275218
DOI:	10.18632/oncotarget.8864
Journal or Publication Title:	Oncotarget
Volume:	7
Number:	21
Page Range:	S. 30523 - 30536
Date:	2016
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ANTIBODY-DRUG CONJUGATE; KI-1 ANTIGEN; MONOCLONAL-ANTIBODY; VARIANT CD30; SOLUBLE CD30; T-CELLS; LYMPHOMA; DISEASE; INFLAMMATION; BIOMARKERS Multiple languages Oncology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27521