title: CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma.
abstract: The CD20-targeting monoclonal antibody rituximab is an established component of immunochemotherapeutic regimens against B-cell lymphomas, where its coadministration with conventional anticancer agents has significantly improved long-term outcome. However, the cellular mechanisms by which rituximab exerts its antilymphoma activity are only partially understood. We show here that rituximab induces typical features of cellular senescence, a long-term growth arrest of viable cells with distinct biologic properties, in established B-cell lymphoma cell lines as well as primary transformed B cells. In addition, rituximab-based immunotherapy sensitized lymphoma cells to senescence induction by the chemotherapeutic compound adriamycin (a.k.a. doxorubicin), and, to a lesser extent, by the antimicrotubule agent vincristine. Anti-CD20 treatment further enhanced secretion of senescence-associated cytokines, and augmented the DNA damage response signaling cascade triggered by adriamycin. As the underlying prosenescence mechanism, we found intracellular reactive oxygen species (ROS) levels to be elevated in response to rituximab, and, in turn, the ROS scavenger N-acetylcysteine to largely abrogate rituximab-mediated senescence. Our results, further supported by gene set enrichment analyses in a clinical data set of chronic lymphocytic leukemia patient samples exposed to a rituximab-containing treatment regimen, provide important mechanistic insights into the biologic complexity of anti-CD20-evoked tumor responses, and unveil cellular senescence as a hitherto unrecognized effector principle of the antibody component in lymphoma immunochemotherapy. Mol Cancer Ther; 15(5); 1074-81. ©2016 AACR.
authors.affiliation: Charité - University Medical Center, Medical Department of Hematology, Oncology and Tumor Immunology, Campus Virchow Clinic, Berlin, Germany. Charité - University Medical Center, Molekulares Krebsforschungszentrum, Berlin, Germany.
authors.forename: J Henry M
authors.initials: JH
authors.lastname: Däbritz
authors.affiliation: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Charité - University Medical Center, Molekulares Krebsforschungszentrum, Berlin, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Milanovic
authors.affiliation: Charité - University Medical Center, Molekulares Krebsforschungszentrum, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schönlein
authors.affiliation: Julius Maximilians University Würzburg, Department of Pathology, Würzburg, Germany.
authors.forename: Mathias T
authors.initials: MT
authors.lastname: Rosenfeldt
authors.affiliation: Charité - University Medical Center, Molekulares Krebsforschungszentrum, Berlin, Germany.
authors.forename: Jan R
authors.initials: JR
authors.lastname: Dörr
authors.affiliation: Charité - University Medical Center, Gynecological Tumor Immunology, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Kaufmann
authors.affiliation: Charité - University Medical Center, Medical Department of Hematology, Oncology and Tumor Immunology, Campus Virchow Clinic, Berlin, Germany. Charité - University Medical Center, Molekulares Krebsforschungszentrum, Berlin, Germany. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.affiliation: Charité - University Medical Center, Medical Department of Hematology, Oncology and Tumor Immunology, Campus Virchow Clinic, Berlin, Germany. Charité - University Medical Center, Molekulares Krebsforschungszentrum, Berlin, Germany. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Germany. Berlin Institute of Health (BIH), Berlin, Germany. clemens.schmitt@charite.de.
authors.forename: Clemens A
authors.initials: CA
authors.lastname: Schmitt
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D016207:Cytokines; D017382:Reactive Oxygen Species