Universität zu Köln

Lobastova, Liudmila, Lettau, Marcus ORCID: 0000-0002-3824-9923, Babatz, Felix, de Oliveira, Thais Dolzany, Nguyen, Phuong-Hien, Pauletti, Bianca Alves, Schauss, Astrid C., Duerkop, Horst, Janssen, Ottmar, Paes Leme, Adriana F., Hallek, Michael and Hansen, Hinrich P. (2021). CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin. Front. Cell. Dev. Biol., 9. LAUSANNE: FRONTIERS MEDIA SA. ISSN 2296-634X

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Abstract

CD30, a member of the TNF receptor superfamily, is selectively expressed on a subset of activated lymphocytes and on malignant cells of certain lymphomas, such as classical Hodgkin Lymphoma (cHL), where it activates critical bystander cells in the tumor microenvironment. Therefore, it is not surprising that the CD30 antibody-drug conjugate Brentuximab Vedotin (BV) represents a powerful, FDA-approved treatment option for CD30(+) hematological malignancies. However, BV also exerts a strong anti-cancer efficacy in many cases of diffuse large B cell lymphoma (DLBCL) with poor CD30 expression, even when lacking detectable CD30(+) tumor cells. The mechanism remains enigmatic. Because CD30 is released on extracellular vesicles (EVs) from both, malignant and activated lymphocytes, we studied whether EV-associated CD30 might end up in CD30(-) tumor cells to provide binding sites for BV. Notably, CD30(+) EVs bind to various DLBCL cell lines as well as to the FITC-labeled variant of the antibody-drug conjugate BV, thus potentially conferring the BV binding also to CD30(-) cells. Confocal microscopy and imaging cytometry studies revealed that BV binding and uptake depend on CD30(+) EVs. Since BV is only toxic toward CD30(-) DLBCL cells when CD30(+) EVs support its uptake, we conclude that EVs not only communicate within the tumor microenvironment but also influence cancer treatment. Ultimately, the CD30-based BV not only targets CD30(+) tumor cell but also CD30(-) DLBCL cells in the presence of CD30(+) EVs. Our study thus provides a feasible explanation for the clinical impact of BV in CD30(-) DLBCL and warrants confirming studies in animal models.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lobastova, Liudmila UNSPECIFIED UNSPECIFIED UNSPECIFIED Lettau, Marcus UNSPECIFIED orcid.org/0000-0002-3824-9923 UNSPECIFIED Babatz, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED de Oliveira, Thais Dolzany UNSPECIFIED UNSPECIFIED UNSPECIFIED Nguyen, Phuong-Hien UNSPECIFIED UNSPECIFIED UNSPECIFIED Pauletti, Bianca Alves UNSPECIFIED UNSPECIFIED UNSPECIFIED Schauss, Astrid C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Duerkop, Horst UNSPECIFIED UNSPECIFIED UNSPECIFIED Janssen, Ottmar UNSPECIFIED UNSPECIFIED UNSPECIFIED Paes Leme, Adriana F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansen, Hinrich P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-590122
DOI:	10.3389/fcel.2021.698503
Journal or Publication Title:	Front. Cell. Dev. Biol.
Volume:	9
Date:	2021
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	2296-634X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MONOCLONAL-ANTIBODY; EXPRESSION; RESPONSES; LYMPHOMA Multiple languages Cell Biology; Developmental Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59012