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

  • Nat Commun. 2023 Sep 26;14(1):5983. doi: 10.1038/s41467-023-41737-1.
Chun Wai Wong  1  2 ,  Christos Evangelou  1  2 ,  Kieran N Sefton  #  1  2 ,  Rotem Leshem  #  1  2 ,  Wei Zhang  1 ,  Vishaka Gopalan  3 ,  Sorayut Chattrakarn  1  2 ,  Macarena Lucia Fernandez Carro  1  2 ,  Erez Uzuner  1  2 ,  Holly Mole  1 ,  Daniel J Wilcock  1 ,  Michael P Smith  1 ,  Kleita Sergiou  1 ,  Brian A Telfer  1 ,  Dervla T Isaac  4 ,  Chang Liu  4 ,  Nicholas R Perl  4 ,  Kerrie Marie  1 ,  Paul Lorigan  1  5 ,  Kaye J Williams  1 ,  Patricia E Rao  6 ,  Raghavendar T Nagaraju  1  7 ,  Mario Niepel  4 ,  Adam F L Hurlstone  8  9
Affiliations
  • 1. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK.
  • 2. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK.
  • 3. Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, 20814, USA.
  • 4. Ribon Therapeutics Inc., 35 Cambridge Park Drive, Suite 300, Cambridge, MA, 02140, USA.
  • 5. Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
  • 6. Patricia E. Rao Consulting, Acton, MA, 01720, USA.
  • 7. Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, UK.
  • 8. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. [email protected].
  • 9. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. [email protected].
  • # Contributed equally.
PMID: 37752135 DOI: 10.1038/s41467-023-41737-1
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.

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