Down-regulation of A20 promotes immune escape of lung adenocarcinomas

Sci Transl Med. 2021 Jul 7;13(601):eabc3911. doi: 10.1126/scitranslmed.abc3911.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • B7-H1 Antigen
  • Interferon-gamma
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3