IRF8 regulates efficacy of therapeutic anti‐CD20 monoclonal antibodies - Archive ouverte HAL Access content directly
Journal Articles European Journal of Immunology Year : 2022

IRF8 regulates efficacy of therapeutic anti‐CD20 monoclonal antibodies

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Ferdinand Roesch
Hugo Mouquet

Abstract

Anti-CD20 monoclonal antibodies such as Rituximab, Ofatumumab, and Obinutuzumab are widely used to treat lymphomas and autoimmune diseases. They act by depleting B cells, mainly through Fc-dependent effectors functions. Some patients develop resistance to treatment but the underlying mechanisms are poorly understood. Here, we performed a genome-wide CRISPR/Cas9 screen to identify genes regulating the efficacy of anti-CD20 antibodies. We used as a model the killing of RAJI B cells by Rituximab through complement-dependent-cytotoxicity (CDC). As expected, the screen identified MS4A1, encoding CD20, the target of Rituximab. Among other identified genes, the role of Interferon Regulatory Factor 8 (IRF8) was validated in two B-cell lines. IRF8 KO also decreased the efficacy of antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) induced by anti-CD20 antibodies. We further show that IRF8 is necessary for efficient CD20 transcription. Levels of IRF8 and CD20 RNA or proteins correlated in normal B cells and in hundreds of malignant B cells. Therefore, IRF8 regulates CD20 expression and controls the depleting capacity of anti-CD20 antibodies. Our results bring novel insights into the pathways underlying resistance to CD20-targeting immunotherapies.

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hal-03833626 , version 1 (28-10-2022)

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Ludivine Grzelak, Ferdinand Roesch, Amaury Vaysse, Anne Biton, Rachel Legendre, et al.. IRF8 regulates efficacy of therapeutic anti‐CD20 monoclonal antibodies. European Journal of Immunology, 2022, 52 (10), pp.1648-1661. ⟨10.1002/eji.202250037⟩. ⟨hal-03833626⟩
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