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

Author

Listed:
  • Maurizio Mangolini

    (University of Cambridge
    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
    University of Cambridge)

  • Giorgia Giachetti

    (University of Cambridge
    University of Cambridge)

  • Junyan Lu

    (European Molecular Biology Laboratory (EMBL)
    Molecular Medicine Partnership Unit (MMPU))

  • 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
    National Center for Tumor Diseases and German Cancer, Research Centre)

  • Irina Mohorianu

    (University of Cambridge)

  • Clive D’Santos

    (University of Cambridge)

  • Silvia Deaglio

    (University of Turin)

  • Daniel J. Hodson

    (University of Cambridge
    University of Cambridge)

  • Jose I. Martin-Subero

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Ingo Ringshausen

    (University of Cambridge
    University of Cambridge)

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.

Suggested Citation

  • Maurizio Mangolini & Alba Maiques-Diaz & Stella Charalampopoulou & Elena Gerhard-Hartmann & Johannes Bloehdorn & Andrew Moore & Giorgia Giachetti & Junyan Lu & Valar Nila Roamio Franklin & Chandra Sek, 2022. "Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33739-2
    DOI: 10.1038/s41467-022-33739-2
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    References listed on IDEAS

    as
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