Down-regulation of A20 promotes immune escape of lung adenocarcinomas
Kristina Breitenecker, Monika Homolya, Andreea Corina Luca, Veronika Lang, Christoph Trenk, Georg Petroczi, Julian Mohrherr, Jaqueline Horvath, Stefan Moritsch, Lisa Haas, Margarita Kurnaeva, Robert Eferl, Dagmar Stoiber, Richard Moriggl, Martin Bilban, Anna C. Obenauf, Christiane Ferran, Balázs Döme, Viktória László, Balázs Győrffy, Katalin Dezső, Judit Moldvay, Emilio Casanova, Herwig P. Moll
Abstract
T cell-mediated immune surveillance in patients with lung cancer and in mouse models. In mice, we observed that this effect was completely dependent on increased cellular sensitivity to interferon-γ (IFN-γ) signaling by aberrant activation of TANK-binding kinase 1 (TBK1) and increased downstream expression and activation of signal transducer and activator of transcription 1 (STAT1). Interrupting this autocrine feed forward loop by knocking out IFN-α/β receptor completely restored infiltration of cytotoxic T cells and rescued loss of A20 depending tumorigenesis. Downstream of STAT1, programmed death ligand 1 (PD-L1) was highly expressed in A20 knockout lung tumors. Accordingly, immune checkpoint blockade (ICB) treatment was highly efficient in mice harboring A20-deficient lung tumors. Furthermore, an A20 loss-of-function gene expression signature positively correlated with survival of melanoma patients treated with anti-programmed cell death protein 1. Together, we have identified A20 as a master immune checkpoint regulating the TBK1-STAT1-PD-L1 axis that may be exploited to improve ICB therapy in patients with lung adenocarcinoma.