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PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models

Author

Listed:
  • Chun Wai Wong

    (The University of Manchester
    The University of Manchester)

  • Christos Evangelou

    (The University of Manchester
    The University of Manchester)

  • Kieran N. Sefton

    (The University of Manchester
    The University of Manchester)

  • Rotem Leshem

    (The University of Manchester
    The University of Manchester)

  • Wei Zhang

    (The University of Manchester)

  • Vishaka Gopalan

    (National Cancer Institute)

  • Sorayut Chattrakarn

    (The University of Manchester
    The University of Manchester)

  • Macarena Lucia Fernandez Carro

    (The University of Manchester
    The University of Manchester)

  • Erez Uzuner

    (The University of Manchester
    The University of Manchester)

  • Holly Mole

    (The University of Manchester)

  • Daniel J. Wilcock

    (The University of Manchester)

  • Michael P. Smith

    (The University of Manchester)

  • Kleita Sergiou

    (The University of Manchester)

  • Brian A. Telfer

    (The University of Manchester)

  • Dervla T. Isaac

    (Ribon Therapeutics Inc.)

  • Chang Liu

    (Ribon Therapeutics Inc.)

  • Nicholas R. Perl

    (Ribon Therapeutics Inc.)

  • Kerrie Marie

    (The University of Manchester)

  • Paul Lorigan

    (The University of Manchester
    The Christie NHS Foundation Trust)

  • Kaye J. Williams

    (The University of Manchester)

  • Patricia E. Rao

    (Patricia E. Rao Consulting)

  • Raghavendar T. Nagaraju

    (The University of Manchester
    The Christie NHS Foundation Trust)

  • Mario Niepel

    (Ribon Therapeutics Inc.)

  • Adam F. L. Hurlstone

    (The University of Manchester
    The University of Manchester)

Abstract

Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFNγ exposure confers resistance to immunotherapy targeting PD-1 (α-PD-1) in immunocompetent female mice. We observe upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in chronic IFNγ-treated cancer cell models, in patient melanoma with elevated IFNG expression, and in melanoma cell cultures from ICBT-progressing lesions characterised by elevated IFNγ signalling. Effector T cell infiltration is enhanced in tumours derived from cells pre-treated with IFNγ in immunocompetent female mice when PARP14 is pharmacologically inhibited or knocked down, while the presence of regulatory T cells is decreased, leading to restoration of α-PD-1 sensitivity. Finally, we determine that tumours which spontaneously relapse in immunocompetent female mice following α-PD-1 therapy upregulate IFNγ signalling and can also be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.

Suggested Citation

  • Chun Wai Wong & Christos Evangelou & Kieran N. Sefton & Rotem Leshem & Wei Zhang & Vishaka Gopalan & Sorayut Chattrakarn & Macarena Lucia Fernandez Carro & Erez Uzuner & Holly Mole & Daniel J. Wilcock, 2023. "PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41737-1
    DOI: 10.1038/s41467-023-41737-1
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