CD30 on extracellular vesicles from malignant Hodgkin cells supports damaging of CD30 ligand-expressing bystander cells with Brentuximab-Vedotin, in vitro.
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.
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Hinrich P
HP
Hansen
Department of Biochemistry, University Kiel, Kiel, Germany.
Ahmad
A
Trad
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Maria
M
Dams
Department of Dermatology, University of Cologne, Cologne, Germany.
Paola
P
Zigrino
BioZyme Inc., Apex, North Carolina, USA.
Marcia
M
Moss
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Maximilian
M
Tator
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Gisela
G
Schön
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Patricia C
PC
Grenzi
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Daniel
D
Bachurski
Brazilian Biosciences National Laboratory, LNBio, CNPEM, Campinas, Brazil.
Bruno
B
Aquino
Pathodiagnostik Berlin, Berlin, Germany.
Horst
H
Dürkop
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Katrin S
KS
Reiners
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Michael
M
von Bergwelt-Baildon
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Michael
M
Hallek
Department of Biochemistry, University Kiel, Kiel, Germany.
Joachim
J
Grötzinger
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Andreas
A
Engert
Brazilian Biosciences National Laboratory, LNBio, CNPEM, Campinas, Brazil.
Adriana F
AF
Paes Leme
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Elke
E
Pogge von Strandmann
D000072197:ADAM10 Protein / Q000378:metabolism; D015153:Blotting, Western; D000079963:Brentuximab Vedotin; D024201:Bystander Effect / Q000187:drug effects*; D053285:CD30 Ligand / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D000067128:Extracellular Vesicles / Q000378:metabolism*; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D017730:Ki-1 Antigen / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects
D053285:CD30 Ligand; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D000079963:Brentuximab Vedotin; D000072197:ADAM10 Protein
ADAM10; Brentuximab-Vedotin; CD30; Hodgkin lymphoma; extracellular vesicle