[Research Articles] Down-regulation of A20 promotes immune escape of lung adenocarcinomas
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- (IFN-) 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 ax...
Source: Science Translational Medicine - Category: Biomedical Science Authors: Breitenecker, K., Homolya, M., Luca, A. C., Lang, V., Trenk, C., Petroczi, G., Mohrherr, J., Horvath, J., Moritsch, S., Haas, L., Kurnaeva, M., Eferl, R., Stoiber, D., Moriggl, R., Bilban, M., Obenauf, A. C., Ferran, C., Dome, B., Laszlo, V., Gyorffy, B., Tags: Research Articles Source Type: research
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