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

Wong, C. W.; Evangelou, C.; Sefton, K. N.; Leshem, R.; Sergiou, K.; Fernandez Carro, M. L.; Uzuner, E.; Mole, H.; Telfer, B. A.; Wilcock, D. J.; Smith, M. P.; Kunii, K.; Perl, N. R.; Lorigan, P.; Williams, K. J.; Rao, P. E.; Nagaraju, R. T.; Niepel, M.; Hurlstone, A. F. L.

doi:10.1101/2022.11.18.517143

bioRxiv · 10.1101/2022.11.18.517143

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

Wong, C. W.·Evangelou, C.·Sefton, K. N.·Leshem, R.·Sergiou, K.·Fernandez Carro, M. L.·Uzuner, E.·Mole, H.·Telfer, B. A.·Wilcock, D. J.·Smith, M. P.·Kunii, K.·Perl, N. R.·Lorigan, P.·Williams, K. J.·Rao, P. E.·Nagaraju, R. T.·Niepel, M.·Hurlstone, A. F. L.

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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.

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Wong, C. W., Evangelou, C., Sefton, K. N., Leshem, R., Sergiou, K., Fernandez Carro, M. L., Uzuner, E., Mole, H., Telfer, B. A., Wilcock, D. J., Smith, M. P., Kunii, K., Perl, N. R., Lorigan, P., Williams, K. J., Rao, P. E., Nagaraju, R. T., Niepel, M., Hurlstone, A. F. L.. 2022-11-18. PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance. https://doi.org/10.1101/2022.11.18.517143

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