Non-canonical NF-?B Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy.

ABSTRACT: The NF-?B pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-?B pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-?B pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-?B deficiency promoted IR-induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-?B 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-?B pathway resulted in decreased type I IFN expression. Administration of a specific inhibitor of the non-canonical NF-?B pathway enhanced the anti-tumor effect of IR in murine models. These findings reveal the potentially interactive roles for canonical and non-canonical NF-?B pathways in IR-induced STING-IFN production and provide an alternative strategy to improve cancer radiotherapy.

SUBMITTER: Hou Y 

PROVIDER: S-EPMC6775781 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature