CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma
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CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma. / Yu, Yong; Schönlein, Martin; Kaufmann, Andreas M; Dörken, Bernd; Schmitt, Clemens A.
in: MOL CANCER THER, Jahrgang 15, Nr. 5, 05.2016, S. 1074-81.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma
AU - Yu, Yong
AU - Schönlein, Martin
AU - Kaufmann, Andreas M
AU - Dörken, Bernd
AU - Schmitt, Clemens A
N1 - ©2016 American Association for Cancer Research.
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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.
KW - Antibodies, Monoclonal/pharmacology
KW - Antigens, CD20/metabolism
KW - Antineoplastic Agents/pharmacology
KW - Apoptosis/drug effects
KW - Cell Cycle/drug effects
KW - Cell Line, Transformed
KW - Cell Line, Tumor
KW - Cellular Senescence/drug effects
KW - Cytokines/metabolism
KW - DNA Damage
KW - Humans
KW - Lymphoma, B-Cell/genetics
KW - Reactive Oxygen Species/metabolism
U2 - 10.1158/1535-7163.MCT-15-0627
DO - 10.1158/1535-7163.MCT-15-0627
M3 - SCORING: Journal article
C2 - 26880268
VL - 15
SP - 1074
EP - 1081
JO - MOL CANCER THER
JF - MOL CANCER THER
SN - 1535-7163
IS - 5
ER -