PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance

Abstract

Adaptive resistance limits immune checkpoint blockade therapy (ICBT) response duration and magnitude. Interferon {gamma} (IFN{gamma}), a critical cytokine that promotes cellular immunity, also induces adaptive resistance to ICBT. Using syngeneic mouse tumour models, we confirmed that chronic IFN{gamma} exposure confers resistance to anti-Programmed cell death protein 1 (-PD-1) therapy. We identified consistent upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in both chronic IFN{gamma}-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 IFN{gamma} and decreased the presence of regulatory T cells, leading to restoration of -PD-1 sensitivity. Finally, we determined that tumours which spontaneously relapsed following -PD-1 therapy could be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFN{gamma}-driven ICBT resistance.