Non-canonical NF-κB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy

Yuzhu Hou, Hua Liang, Enyu Rao, Wenxin Zheng, Xiaona Huang, Liufu Deng, Yuan Zhang, Xinshuang Yu, Meng Xu, Helena Mauceri, Ainhoa Arina, Ralph R. Weichselbaum, Yang-Xin Fu

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

The NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-κB pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-κB pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-κB deficiency promoted IR-induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-κB signaling in dendritic cells (DCs) was activated by the STING sensor-dependent DNA-sensing pathway. By suppressing recruitment of the transcription factor RelA onto the Ifnb promoter, activation of the non-canonical NF-κB pathway resulted in decreased type I IFN expression. Administration of a specific inhibitor of the non-canonical NF-κB pathway enhanced the anti-tumor effect of IR in murine models. These findings reveal the potentially interactive roles for canonical and non-canonical NF-κB pathways in IR-induced STING-IFN production and provide an alternative strategy to improve cancer radiotherapy. It is known that the NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and the radioresistance of tumor cells. Hou et al. demonstrate that the deficiency of non-canonical NF-κB, but not canonical NF-κB, promotes radiation-induced anti-tumor immunity by regulating the STING-mediated type I IFN expression.

Original languageEnglish (US)
Pages (from-to)490-503.e4
JournalImmunity
Volume49
Issue number3
DOIs
StatePublished - Sep 18 2018

Keywords

  • DNA sensing
  • STING
  • dendritic cells
  • non-canonical NF-κB
  • radiotherapy
  • type I IFNs

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Hou, Y., Liang, H., Rao, E., Zheng, W., Huang, X., Deng, L., Zhang, Y., Yu, X., Xu, M., Mauceri, H., Arina, A., Weichselbaum, R. R., & Fu, Y-X. (2018). Non-canonical NF-κB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy. Immunity, 49(3), 490-503.e4. https://doi.org/10.1016/j.immuni.2018.07.008