TY - CONF
T1 - Abstract 625: PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance
AU - Wong, Chun Wai
AU - Evangelou, Christos
AU - Sefton, Kieran N.
AU - Leshem, Rotem
AU - Sergiou, Kleita
AU - Carro, Macarena Lucia Fernandez
AU - Uzuner, Erez
AU - Mole, Holly
AU - Telfer, Brian A.
AU - Wilcock, Daniel J.
AU - Smith, Michael P.
AU - Kunii, Kaiko
AU - Perl, Nicholas R.
AU - Lorigan, Paul
AU - Williams, Kaye J.
AU - Rao, Patricia E.
AU - Nagaraju, Raghavendar T.
AU - Niepel, Mario
AU - Hurlstone, Adam F.
PY - 2023/4/1
Y1 - 2023/4/1
N2 - 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 tumor 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 tumors 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 tumors which spontaneously relapsed following α-PD-1 therapy could be re-sensitized upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.Citation Format: Chun Wai Wong, Christos Evangelou, Kieran N. Sefton, Rotem Leshem, Kleita Sergiou, Macarena Lucia Fernandez Carro, Erez Uzuner, Holly Mole, Brian A. Telfer, Daniel J. Wilcock, Michael P. Smith, Kaiko Kunii, Nicholas R. Perl, Paul Lorigan, Kaye J. Williams, Patricia E. Rao, Raghavendar T. Nagaraju, Mario Niepel, Adam F. Hurlstone. PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 625.
AB - 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 tumor 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 tumors 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 tumors which spontaneously relapsed following α-PD-1 therapy could be re-sensitized upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.Citation Format: Chun Wai Wong, Christos Evangelou, Kieran N. Sefton, Rotem Leshem, Kleita Sergiou, Macarena Lucia Fernandez Carro, Erez Uzuner, Holly Mole, Brian A. Telfer, Daniel J. Wilcock, Michael P. Smith, Kaiko Kunii, Nicholas R. Perl, Paul Lorigan, Kaye J. Williams, Patricia E. Rao, Raghavendar T. Nagaraju, Mario Niepel, Adam F. Hurlstone. PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 625.
UR - https://www.mendeley.com/catalogue/dd175be4-c71f-30bb-9b05-b987e69248d2/
U2 - 10.1158/1538-7445.am2023-625
DO - 10.1158/1538-7445.am2023-625
M3 - Abstract
T2 - AACR Annual Meeting 2023
Y2 - 14 April 2023 through 19 April 2023
ER -