Down-regulation of A20 promotes immune escape of lung adenocarcinomas

Autor:in

Breitenecker, Kristina; Homolya, Monika; Luca, Andreea C.; Lang, V. R.; Trenk, Christoph; Petroczi, Georg; Mohrherr, Julian; Horvath, J.; Moritsch, Stefan; Haas, L.; Kurnaeva, Margarita; Eferl, Robert; Stoiber, Dagmar; Moriggl, Richard; Bilban, Martin; Obenauf, Anna; Ferran, Carme; Doeme, Balazs; laszlo, viktoria; Gyorffy, Balazs; Dezso, Katalin; Moldvay, Judit; Casanova, Emilio; Moll, Herwig

Abstrakt

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-gamma (IFN-gamma) 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-alpha/beta 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.

Dokumententyp

Originalarbeit

DOI

10.1126/scitranslmed.abc3911

PubMed ID

MEDLINE:34233950