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

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, Michael P Smith, Kleita Sergiou, Brian A Telfer, Dervla T Isaac, Chang Liu, Nicholas R Perl, Kerrie Marie, Paul Lorigan, Kaye J WilliamsPatricia E Rao, Raghavendar T Nagaraju, Mario Niepel, Adam F L Hurlstone

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number5983
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 26 Sept 2023

Keywords

  • Female
  • Humans
  • Animals
  • Mice
  • Immune Checkpoint Inhibitors/pharmacology
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma
  • Neoplasm Recurrence, Local
  • Melanoma
  • Disease Models, Animal
  • Poly(ADP-ribose) Polymerases

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