Oncotarget

Research Papers:

CD30 on extracellular vesicles from malignant Hodgkin cells supports damaging of CD30 ligand-expressing bystander cells with Brentuximab-Vedotin, in vitro

Hinrich P. Hansen _, Ahmad Trad, Maria Dams, Paola Zigrino, Marcia Moss, Maximilian Tator, Gisela Schön, Patricia C Grenzi, Daniel Bachurski, Bruno Aquino, Horst Dürkop, Katrin S Reiners, Michael von Bergwelt-Baildon, Michael Hallek, Joachim Grötzinger, Andreas Engert, Adriana F Paes Leme and Elke Pogge von Strandmann

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Oncotarget. 2016; 7:30523-30535. https://doi.org/10.18632/oncotarget.8864

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Abstract

Hinrich P. Hansen1, Ahmad Trad2, Maria Dams1, Paola Zigrino3, Marcia Moss4, Maximilian Tator1, Gisela Schön1, Patricia C Grenzi1, Daniel Bachurski1, Bruno Aquino5, Horst Dürkop6, Katrin S Reiners1, Michael von Bergwelt-Baildon1, Michael Hallek1, Joachim Grötzinger2, Andreas Engert1, Adriana F Paes Leme5, Elke Pogge von Strandmann1

1Department of Internal Medicine I, University of Cologne, Cologne, Germany

2Department of Biochemistry, University Kiel, Kiel, Germany

3Department of Dermatology, University of Cologne, Cologne, Germany

4BioZyme Inc., Apex, North Carolina, USA

5Brazilian Biosciences National Laboratory, LNBio, CNPEM, Campinas, Brazil

6Pathodiagnostik Berlin, Berlin, Germany

Correspondence to:

Hinrich P. Hansen, e-mail: [email protected]

Keywords: Hodgkin lymphoma, extracellular vesicle, CD30, ADAM10, Brentuximab-Vedotin

Received: January 11, 2016     Accepted: March 31, 2016     Published: April 20, 2016

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.


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