CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin
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 surpris...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2021-07-01
|
Series: | Frontiers in Cell and Developmental Biology |
Subjects: | |
Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.698503/full |
id |
doaj-ee4ad5abc83c476f806f4f05d2d13b45 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Liudmila Lobastova Liudmila Lobastova Liudmila Lobastova Liudmila Lobastova Marcus Lettau Marcus Lettau Felix Babatz Thais Dolzany de Oliveira Thais Dolzany de Oliveira Thais Dolzany de Oliveira Thais Dolzany de Oliveira Phuong-Hien Nguyen Phuong-Hien Nguyen Phuong-Hien Nguyen Phuong-Hien Nguyen Bianca Alves Pauletti Astrid C. Schauss Horst Dürkop Ottmar Janssen Adriana F. Paes Leme Michael Hallek Michael Hallek Michael Hallek Michael Hallek Hinrich P. Hansen Hinrich P. Hansen Hinrich P. Hansen Hinrich P. Hansen |
spellingShingle |
Liudmila Lobastova Liudmila Lobastova Liudmila Lobastova Liudmila Lobastova Marcus Lettau Marcus Lettau Felix Babatz Thais Dolzany de Oliveira Thais Dolzany de Oliveira Thais Dolzany de Oliveira Thais Dolzany de Oliveira Phuong-Hien Nguyen Phuong-Hien Nguyen Phuong-Hien Nguyen Phuong-Hien Nguyen Bianca Alves Pauletti Astrid C. Schauss Horst Dürkop Ottmar Janssen Adriana F. Paes Leme Michael Hallek Michael Hallek Michael Hallek Michael Hallek Hinrich P. Hansen Hinrich P. Hansen Hinrich P. Hansen Hinrich P. Hansen CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin Frontiers in Cell and Developmental Biology tumor microenvironment cellular crosstalk immune therapy antibody-drug conjugate extracellular vesicle |
author_facet |
Liudmila Lobastova Liudmila Lobastova Liudmila Lobastova Liudmila Lobastova Marcus Lettau Marcus Lettau Felix Babatz Thais Dolzany de Oliveira Thais Dolzany de Oliveira Thais Dolzany de Oliveira Thais Dolzany de Oliveira Phuong-Hien Nguyen Phuong-Hien Nguyen Phuong-Hien Nguyen Phuong-Hien Nguyen Bianca Alves Pauletti Astrid C. Schauss Horst Dürkop Ottmar Janssen Adriana F. Paes Leme Michael Hallek Michael Hallek Michael Hallek Michael Hallek Hinrich P. Hansen Hinrich P. Hansen Hinrich P. Hansen Hinrich P. Hansen |
author_sort |
Liudmila Lobastova |
title |
CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin |
title_short |
CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin |
title_full |
CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin |
title_fullStr |
CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin |
title_full_unstemmed |
CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin |
title_sort |
cd30-positive extracellular vesicles enable the targeting of cd30-negative dlbcl cells by the cd30 antibody-drug conjugate brentuximab vedotin |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2021-07-01 |
description |
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. |
topic |
tumor microenvironment cellular crosstalk immune therapy antibody-drug conjugate extracellular vesicle |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.698503/full |
work_keys_str_mv |
AT liudmilalobastova cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT liudmilalobastova cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT liudmilalobastova cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT liudmilalobastova cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT marcuslettau cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT marcuslettau cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT felixbabatz cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT thaisdolzanydeoliveira cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT thaisdolzanydeoliveira cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT thaisdolzanydeoliveira cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT thaisdolzanydeoliveira cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT phuonghiennguyen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT phuonghiennguyen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT phuonghiennguyen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT phuonghiennguyen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT biancaalvespauletti cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT astridcschauss cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT horstdurkop cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT ottmarjanssen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT adrianafpaesleme cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT michaelhallek cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT michaelhallek cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT michaelhallek cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT michaelhallek cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT hinrichphansen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT hinrichphansen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT hinrichphansen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin AT hinrichphansen cd30positiveextracellularvesiclesenablethetargetingofcd30negativedlbclcellsbythecd30antibodydrugconjugatebrentuximabvedotin |
_version_ |
1721247501605928960 |
spelling |
doaj-ee4ad5abc83c476f806f4f05d2d13b452021-07-30T13:24:52ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-07-01910.3389/fcell.2021.698503698503CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab VedotinLiudmila Lobastova0Liudmila Lobastova1Liudmila Lobastova2Liudmila Lobastova3Marcus Lettau4Marcus Lettau5Felix Babatz6Thais Dolzany de Oliveira7Thais Dolzany de Oliveira8Thais Dolzany de Oliveira9Thais Dolzany de Oliveira10Phuong-Hien Nguyen11Phuong-Hien Nguyen12Phuong-Hien Nguyen13Phuong-Hien Nguyen14Bianca Alves Pauletti15Astrid C. Schauss16Horst Dürkop17Ottmar Janssen18Adriana F. Paes Leme19Michael Hallek20Michael Hallek21Michael Hallek22Michael Hallek23Hinrich P. Hansen24Hinrich P. Hansen25Hinrich P. Hansen26Hinrich P. Hansen27Department I of Internal Medicine, University of Cologne, Cologne, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyCECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, GermanyInstitute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Hematology, University Hospital Schleswig-Holstein, Kiel, GermanyCECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Imaging Facility, Cologne, GermanyDepartment I of Internal Medicine, University of Cologne, Cologne, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyCECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, GermanyDepartment I of Internal Medicine, University of Cologne, Cologne, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyCECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, GermanyLaboratório de Espectrometria de Massas, Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas, BrazilCECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Imaging Facility, Cologne, GermanyPathodiagnostik Berlin MVZ GmbH Berlin, Berlin, GermanyInstitute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyLaboratório de Espectrometria de Massas, Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas, BrazilDepartment I of Internal Medicine, University of Cologne, Cologne, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyCECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, GermanyDepartment I of Internal Medicine, University of Cologne, Cologne, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyCECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, GermanyCD30, 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.698503/fulltumor microenvironmentcellular crosstalkimmune therapyantibody-drug conjugateextracellular vesicle |