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, f...Continue Reading
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