CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma

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 -