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

Maurizio Mangolini, Alba Maiques-Diaz, Stella Charalampopoulou, Elena Gerhard-Hartmann, Johannes Bloehdorn, Andrew Moore, Giorgia Giachetti, Junyan Lu, Valar Nila Roamio Franklin, Chandra Sekkar Reddy Chilamakuri, Ilias Moutsopoulos, Andreas Rosenwald, Stephan Stilgenbauer, Thorsten Zenz, Irina Mohorianu, Clive D’Santos, Silvia Deaglio, Daniel J. Hodson, Jose I. Martin-Subero and Ingo Ringshausen ()
Additional contact information
Maurizio Mangolini: University of Cambridge
Alba Maiques-Diaz: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Stella Charalampopoulou: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Elena Gerhard-Hartmann: Pathologisches Institut Universität Würzburg
Johannes Bloehdorn: Ulm University
Andrew Moore: University of Cambridge
Giorgia Giachetti: University of Cambridge
Junyan Lu: European Molecular Biology Laboratory (EMBL)
Valar Nila Roamio Franklin: University of Cambridge
Chandra Sekkar Reddy Chilamakuri: University of Cambridge
Ilias Moutsopoulos: University of Cambridge
Andreas Rosenwald: Pathologisches Institut Universität Würzburg
Stephan Stilgenbauer: Ulm University
Thorsten Zenz: University Hospital Zürich and University of Zürich
Irina Mohorianu: University of Cambridge
Clive D’Santos: University of Cambridge
Silvia Deaglio: University of Turin
Daniel J. Hodson: University of Cambridge
Jose I. Martin-Subero: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Ingo Ringshausen: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33739-2

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