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Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape.

Published version
Peer-reviewed

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Authors

Mangolini, Maurizio 
Charalampopoulou, Stella 
Gerhard-Hartmann, Elena 
Bloehdorn, Johannes  ORCID logo  https://orcid.org/0000-0003-1433-9702

Abstract

Hotspot mutations in the PEST-domain of NOTCH1 and NOTCH2 are recurrently identified in B cell malignancies. To address how NOTCH-mutations contribute to a dismal prognosis, we have generated isogenic primary human tumor cells from patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), differing only in their expression of the intracellular domain (ICD) of NOTCH1 or NOTCH2. Our data demonstrate that both NOTCH-paralogs facilitate immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-γ signaling. In addition, NOTCH-activation causes silencing of the entire HLA-class II locus via epigenetic regulation of the transcriptional co-activator CIITA. Notably, while NOTCH1 and NOTCH2 govern similar transcriptional programs, disease-specific differences in their expression levels can favor paralog-specific selection. Importantly, NOTCH-ICD also strongly down-regulates the expression of CD19, possibly limiting the effectiveness of immune-therapies. These NOTCH-mediated immune escape mechanisms are associated with the expansion of exhausted CD8+ T cells in vivo.

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Keywords

Article, /631/67/68, /692/4028/67/1990/283/1895, /45/15, /45/23, /45/44, /45/88, /96/1, /96/2, /96/31, /96/95, /96/109, /13/51, article

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (203151/A/16/Z)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (17480)
Medical Research Council (MC_PC_17230)
National Institute for Health Research (IS-BRC-1215-20014)