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. Williams, Patricia E. Rao, Raghavendar T. Nagaraju, Mario Niepel and Adam F. L. Hurlstone ()
Additional contact information
Chun Wai Wong: The University of Manchester
Christos Evangelou: The University of Manchester
Kieran N. Sefton: The University of Manchester
Rotem Leshem: The University of Manchester
Wei Zhang: The University of Manchester
Vishaka Gopalan: National Cancer Institute
Sorayut Chattrakarn: The University of Manchester
Macarena Lucia Fernandez Carro: The University of Manchester
Erez Uzuner: 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
Kaye J. Williams: The University of Manchester
Patricia E. Rao: Patricia E. Rao Consulting
Raghavendar T. Nagaraju: The University of Manchester
Mario Niepel: Ribon Therapeutics Inc.
Adam F. L. Hurlstone: The University of Manchester

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41737-1

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