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PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models
Wong, C. W. Evangelou, C. Sefton, K. N. Leshem, R. Zhang, W. Gopalan, V. Chattrakarn, S. Fernandez Carro, M. L. Uzuner, E. Mole, H.
Wong, C. W.
Evangelou, C.
Sefton, K. N.
Leshem, R.
Zhang, W.
Gopalan, V.
Chattrakarn, S.
Fernandez Carro, M. L.
Uzuner, E.
Mole, H.
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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.
Authors
Wong, C. W.
Evangelou, C.
Sefton, K. N.
Leshem, R.
Zhang, W.
Gopalan, V.
Chattrakarn, S.
Fernandez Carro, M. L.
Uzuner, E.
Mole, H.
Wilcock, D. J.
Smith, M. P.
Sergiou, K.
Telfer, B. A.
Isaac, D. T.
Liu, C.
Perl, N. R.
Marie, K.
Lorigan, Paul C
Williams, K. J.
Rao, P. E.
Nagaraju, R. T.
Niepel, M.
Hurlstone, A. F. L.
Evangelou, C.
Sefton, K. N.
Leshem, R.
Zhang, W.
Gopalan, V.
Chattrakarn, S.
Fernandez Carro, M. L.
Uzuner, E.
Mole, H.
Wilcock, D. J.
Smith, M. P.
Sergiou, K.
Telfer, B. A.
Isaac, D. T.
Liu, C.
Perl, N. R.
Marie, K.
Lorigan, Paul C
Williams, K. J.
Rao, P. E.
Nagaraju, R. T.
Niepel, M.
Hurlstone, A. F. L.
Description
Date
2023
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Article
Citation
Wong CW, Evangelou C, Sefton KN, Leshem R, Zhang W, Gopalan V, et al. PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models. Nature communications. 2023 Sep 26;14(1):5983. PubMed PMID: 37752135. Pubmed Central PMCID: PMC10522711 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. Epub 2023/09/27. eng.