Details

Autor(en) / Beteiligte

• Wong, Chun Wai
• Evangelou, Christos
• Sefton, Kieran N.
• Leshem, Rotem
• Zhang, Wei
• Gopalan, Vishaka
• Chattrakarn, Sorayut
• Fernandez Carro, Macarena Lucia
• Uzuner, Erez
• Mole, Holly
• Wilcock, Daniel J.
• Smith, Michael P.
• Sergiou, Kleita
• Telfer, Brian A.
• Isaac, Dervla T.
• Liu, Chang
• Perl, Nicholas R.
• Marie, Kerrie
• Lorigan, Paul
• Williams, Kaye J.
• Rao, Patricia E.
• Nagaraju, Raghavendar T.
• Niepel, Mario
• Hurlstone, Adam F. L.

Titel

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

Ist Teil von

• Nature communications, 2023-09, Vol.14 (1), p.5983-21, Article 5983

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. IFNγ signalling has been described as a potential driver of resistance to immune checkpoint blockade (ICB) therapy. Here the authors report that PARP14 is upregulated in chronic IFNγ-treated cancer cell models and that its inhibition restores response to anti-PD-1 therapy in preclinical cancer models.