CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin.

Autor:	Lobastova L; Department I of Internal Medicine, University of Cologne, Cologne, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany., Lettau M; Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.; Department of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany., Babatz F; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Imaging Facility, Cologne, Germany., de Oliveira TD; Department I of Internal Medicine, University of Cologne, Cologne, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany., Nguyen PH; Department I of Internal Medicine, University of Cologne, Cologne, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany., Pauletti BA; Laboratório de Espectrometria de Massas, Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas, Brazil., Schauss AC; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Imaging Facility, Cologne, Germany., Dürkop H; Pathodiagnostik Berlin MVZ GmbH Berlin, Berlin, Germany., Janssen O; Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, Kiel, Germany., Paes Leme AF; Laboratório de Espectrometria de Massas, Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas, Brazil., Hallek M; Department I of Internal Medicine, University of Cologne, Cologne, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany., Hansen HP; Department I of Internal Medicine, University of Cologne, Cologne, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2021 Jul 30; Vol. 9, pp. 698503. Date of Electronic Publication: 2021 Jul 30 (Print Publication: 2021).
DOI:	10.3389/fcell.2021.698503
Abstrakt:	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. Competing Interests: HD was employed by the company Pathodiagnostik Berlin MVZ GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Lobastova, Lettau, Babatz, de Oliveira, Nguyen, Pauletti, Schauss, Dürkop, Janssen, Paes Leme, Hallek and Hansen.)
Databáze:	MEDLINE
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