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IRF8 regulates efficacy of therapeutic anti-CD20 monoclonal antibodies.
- Source :
-
European journal of immunology [Eur J Immunol] 2022 Oct; Vol. 52 (10), pp. 1648-1661. Date of Electronic Publication: 2022 Sep 07. - Publication Year :
- 2022
-
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.<br /> (© 2022 Wiley-VCH GmbH.)
Details
- Language :
- English
- ISSN :
- 1521-4141
- Volume :
- 52
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- European journal of immunology
- Publication Type :
- Academic Journal
- Accession number :
- 36030374
- Full Text :
- https://doi.org/10.1002/eji.202250037