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PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance
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PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance
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Paper
PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance
2022
Overview
Adaptive resistance limits immune checkpoint blockade therapy (ICBT) response duration and magnitude. Interferon γ (IFNγ), a critical cytokine that promotes cellular immunity, also induces adaptive resistance to ICBT. Using syngeneic mouse tumour models, we confirmed that chronic IFNγ exposure confers resistance to anti-Programmed cell death protein 1 (α-PD-1) therapy. We identified consistent upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in both chronic IFNγ-treated cancer cells and patient melanoma with elevated IFNG expression. Knockdown or pharmacological inhibition of PARP14 increased effector T cell infiltration into tumours derived from cells pre-treated with IFNγ and decreased the presence of regulatory T cells, leading to restoration of α-PD-1 sensitivity. Finally, we determined that tumours which spontaneously relapsed following α-PD-1 therapy could be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.Competing Interest StatementK.K., N.R.P., and M.N are all employees and shareholders of Ribon Therapeutics at the time of data collection. P.E.R. served as a consultant to Ribon Therapeutics. A.H. received research sponsorship from Ribon Therapeutics. All other authors declare no competing interests.Footnotes* All authors have been updated with their corresponding ORCIDs.
Publisher
Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
Subject
