Adaptive resistance limits immune checkpoint blockade therapy (ICBT) response duration and magnitude. Interferon γ (IFN-γ), a critical cytokine that promotes cellular immunity, also induces adaptive resistance to ICBT. Using syngeneic mouse tumour 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 tumours derived from cells pre-treated with IFNγ and decreased the presence of regulatory T cells, leading to restoration of α-PD-1 sensitivity. PARP14-inhibition could potentially increase the activation of STAT1 signalling in tumour cells pre-treated with chronic IFN-γ exposure. We determined that tumours which spontaneously relapsed following α-PD-1 therapy could be re-sensitised upon receiving PARP14 inhibitor treatment. In addition, we found out that T cells pre-treated with PARP14-inhibitor could induce a more pro-inflammatory phenotype, more terminal differentiated, and more proliferative. These established PARP14 as an actionable target to reverse IFN-γ-driven ICBT resistance.
- Cancer-intrinsic resistance
- Interferon
- Checkpoint inhibitor
PARP14 INHIBITION RESTORES PD-1 IMMUNE CHECKPOINT INHIBITOR RESPONSE FOLLOWING IFN-γ-DRIVEN ADAPTIVE RESISTANCE
Wong, C. W. (Author). 31 Dec 2023
Student thesis: Phd