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

Research output: Journal article (peer-reviewed)Journal article

9 Citations (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.

Original languageEnglish
Article numbereabc3911
JournalScience Translational Medicine
Volume13
Issue number601
DOIs
Publication statusPublished - 07 Jul 2021

Keywords

  • Adenocarcinoma of Lung/genetics
  • Animals
  • B7-H1 Antigen/genetics
  • Down-Regulation
  • Humans
  • Interferon-gamma/metabolism
  • Lung Neoplasms/genetics
  • Mice
  • Signal Transduction
  • Tumor Necrosis Factor alpha-Induced Protein 3/genetics

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