Research ArticleLUNG CANCER

Down-regulation of A20 promotes immune escape of lung adenocarcinomas

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Science Translational Medicine  07 Jul 2021:
Vol. 13, Issue 601, eabc3911
DOI: 10.1126/scitranslmed.abc3911

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A checkpoint for lung cancer

Inflammation is a driver of tumor development, and down-regulation or loss of genes required to control inflammation can be protumorigenic. One such gene that may serve as such a controller of inflammation is tumor necrosis factor alpha–induced protein 3 (TNFAIP3), also known as A20. Here, Breitenecker et al. demonstrated that loss of A20 was associated with reduced CD8+ T cell–mediated immune surveillance in both mouse models and in patients with lung cancer. Further, A20 loss was associated with increased tumor burden in mouse models, but these tumors were sensitive to immune checkpoint blockade therapies. Together, these findings suggest that A20 may be a checkpoint in the development of lung adenocarcinoma.

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.

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