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CD20-targeting immunotherapy promotes cellular senescence in B-cell lymphoma

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Item Type:Article
Title:CD20-targeting immunotherapy promotes cellular senescence in B-cell lymphoma
Creators Name:Däbritz, J.H.M. and Yu, Y. and Milanovic, M. and Schönlein, M. and Rosenfeldt, M.T. and Dörr, J.R. and Kaufmann, A.M. and Dörken, B. and Schmitt, C.A.
Abstract:The CD20-targeting monoclonal antibody Rituximab is an established component of immunochemotherapeutic regimens against B-cell lymphomas, where its co-administration with conventional anti-cancer agents has significantly improved long-term outcome. However, the cellular mechanisms by which Rituximab exerts its anti-lymphoma 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 biological 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 (DDR) signaling cascade triggered by Adriamycin. As the underlying pro-senescence mechanism, we found intracellular reactive oxygen species (ROS) levels to be elevated in response to Rituximab, and, in turn, the ROS scavenger N-acetylcysteine (NAC) 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 biological complexity of anti-CD20-evoked tumor responses, and unveil cellular senescence as a hitherto unrecognized effector principle of the antibody component in lymphoma immunochemotherapy.
Keywords:B-Cell Lymphoma, Cellular Senescence, Immunotherapy, Rituximab
Source:Molecular Cancer Therapeutics
Publisher:American Association for Cancer Research
Page Range:1074-1081
Date:May 2016
Official Publication:https://doi.org/10.1158/1535-7163.MCT-15-0627
PubMed:View item in PubMed

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