Olivier Schwartz

People living with HIV suffer from chronic immune activation despite effective antiretroviral therapy. Early after infection, HIV-1 actively replicates in the gut, causing the breakage of the intestinal epithelial barrier and microbial translocation.

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.