IRF8 regulates efficacy of therapeutic anti-CD20 monoclonal antibodies.
CD20 protein
CRISPR/Cas9
DLBCL
IRF8
anti-CD20 monoclonal antibodies
Journal
European journal of immunology
ISSN: 1521-4141
Titre abrégé: Eur J Immunol
Pays: Germany
ID NLM: 1273201
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
29
07
2022
received:
07
06
2022
accepted:
25
08
2022
pubmed:
29
8
2022
medline:
14
10
2022
entrez:
28
8
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36030374
doi: 10.1002/eji.202250037
doi:
Substances chimiques
Antigens, CD20
0
Antineoplastic Agents
0
Interferon Regulatory Factors
0
interferon regulatory factor-8
0
Rituximab
4F4X42SYQ6
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1648-1661Informations de copyright
© 2022 Wiley-VCH GmbH.
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