TY - JOUR
T1 - PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNϒ-drive acquired resistance in preclinical cancer models
AU - Wong, Chun Wai
AU - Evangelou, Christos
AU - Sefton, Kieran N.
AU - Leshem, Rotem
AU - Zhang, Wei
AU - Gopalan, Vishaka
AU - Chattrakarn, Sorayut
AU - Fernandez Carro, Macarena Lucia
AU - Uzuner, Erez
AU - Mole, Holly
AU - Wilcock, Daniel J.
AU - Smith, Michael P.
AU - Sergiou, Kleita
AU - Telfer, Brian a.
AU - Isaac, Dervla T.
AU - Liu, Chang
AU - Perl, Nicholas R.
AU - Marie, Kerrie
AU - Lorigan, Paul
AU - Williams, Kaye J.
AU - Rao, Patricia E.
AU - Nagaraju, Raghavendar T.
AU - Niepel, Mario
AU - Hurlstone, Adam F. L.
PY - 2023/9/26
Y1 - 2023/9/26
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-023-41737-1
DO - 10.1038/s41467-023-41737-1
M3 - Article
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
M1 - 5983
ER -