Down-regulation of A20 promotes immune escape of lung adenocarcinomas

Kristina Breitenecker, Monika Homolya, Andreea C 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, Balazs Dome, Viktoria Laszlo, Balázs GyőrffyKatalin Dezso, Judit Moldvay, Emilio Casanova, Herwig P Moll

Publikation: Beitrag in Fachzeitschrift (peer-reviewed)Artikel in Fachzeitschrift

9 Zitate (Scopus)

Abstract

Inflammation is a well-known driver of lung tumorigenesis. One strategy by which tumor cells escape tight homeostatic control is by decreasing the expression of the potent anti-inflammatory protein tumor necrosis factor alpha-induced protein 3 (TNFAIP3), also known as A20. We observed that tumor cell intrinsic loss of A20 markedly enhanced lung tumorigenesis and was associated with reduced CD8+ 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.

OriginalspracheEnglisch
Aufsatznummereabc3911
FachzeitschriftScience Translational Medicine
Jahrgang13
Ausgabenummer601
DOIs
PublikationsstatusVeröffentlicht - 07 Juli 2021

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