Resistance to complement activation, cell membrane hypersialylation and relapses in chronic lymphocytic leukemia patients treated with rituximab and chemotherapy

Oncotarget
Anne BordronYves Renaudineau

Abstract

The anti-CD20-specific monoclonal antibody rituximab (RTX), in combination with chemotherapy, is commonly used for primary treatment in chronic lymphocytic leukemia (CLL). However, relapses remain important and activation of the complement pathway is one of the mechanisms by which RTX generates the destruction of B cells directly by complement-dependent cytotoxicity (CDC), or indirectly by antibody-dependent cellular phagocytosis. In this study, the RTX capacity to induce CDC was established in 69 untreated CLL patients, this cohort including 34 patients tested before the initiation of RTX-chemotherapy. In vitro CDC-resistance to RTX predicts lower response rates to RTX-chemotherapy and shorter treatment free survival. Furthermore, the predictive value of CDC-resistance was independent from the clinical, cytogenetic and FcγR3A V158F polymorphism status. In contrast, CLL cell resistance to CDC predominates in IGHV unmutated patients and was related to an important α2-6 sialyl transferase activity, which in turn increases cell surface α2-6 hypersialylation. Suspected factors associated with resistance to CDC (CD20, CD55, CD59, factor H, GM1, and sphingomyelin) were not differentially expressed or recruited between the two CLL gro...Continue Reading

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Citations

May 31, 2019·Clinical Reviews in Allergy & Immunology·Anne BordronYves Renaudineau
Jan 31, 2019·Journal for Immunotherapy of Cancer·Cristina BagaceanYves Renaudineau
Apr 25, 2019·Journal for Immunotherapy of Cancer·Marjolaine DebantYves Renaudineau
Sep 10, 2020·Antibodies·Ronald P Taylor, Margaret A Lindorfer
Nov 5, 2020·British Journal of Cancer·Christopher Dobie, Danielle Skropeta
Nov 1, 2020·Antibodies·Josée Golay, Ronald P Taylor
Mar 21, 2020·The American Journal of Pathology·Catherine B XieJordan S Pober

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Methods Mentioned

BETA
FACS
ELISA
density-gradient centrifugation
flow cytometry
PCR

Clinical Trials Mentioned

NCT03294980

Software Mentioned

Survival
SurvMisc R
GraphPad Prism

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