Akademik Veri Yönetim Sistemi
NATURE COMMUNICATIONS, cilt.14, sa.1, 2023 (SCI-Expanded, Scopus)
Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon gamma (IFN gamma), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFN gamma exposure confers resistance to immunotherapy targeting PD-1 (alpha-PD-1) in immunocompetent female mice. We observe upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in chronic IFN gamma-treated cancer cell models, in patient melanoma with elevated IFNG expression, and in melanoma cell cultures from ICBT-progressing lesions characterised by elevated IFN gamma signalling. Effector T cell infiltration is enhanced in tumours derived from cells pre-treated with IFN gamma 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 alpha-PD-1 sensitivity. Finally, we determine that tumours which spontaneously relapse in immunocompetent female mice following alpha-PD-1 therapy upregulate IFN gamma signalling and can also be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFN gamma-driven ICBT resistance.