000K utf8 1100 $c2021 1500 eng 2050 urn:nbn:de:gbv:8:3-2021-00779-2 2051 10.3389/fcell.2021.698503 3000 Lobastova, Liudmila 3010 Babatz, Felix 3010 de Oliveira, Thais Dolzany 3010 Dürkop, Horst 3010 Hallek, Michael 3010 Hansen, Hinrich P 3010 Janssen, Ottmar 3010 Lettau, Marcus 3010 Nguyen, Phuong-Hien 3010 Paes Leme, Adriana F 3010 Pauletti, Bianca Alves 3010 Schauss, Astrid C 4000 CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin [Lobastova, Liudmila] 4209 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. 4950 https://doi.org/10.3389/fcell.2021.698503$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:gbv:8:3-2021-00779-2$xR$3Volltext$534 4961 https://macau.uni-kiel.de/receive/macau_mods_00002072 5051 610 5550 Antibody-drug Conjugate 5550 Cellular Crosstalk 5550 Extracellular Vesicle 5550 immune therapy 5550 Tumor Microenvironment