Feedback regulation of antioxidant transcription factor NFE2L1 and immunostimulatory factor 41BBL mediates the crosstalk between oxidative stress and tumor immunity.

ABSTRACT

Targeting the immune checkpoint to inhibit tumor immune escape, which is one of the fundamental causes of cancer, has become an important strategy for cancer treatment. The molecular mechanism of tumor immune escape involved in the process of spontaneous hepatocellular carcinoma after specifically knocking out NFE2L1, the core regulator of redox homeostasis, in the mouse liver is still unclear. Transcriptome data showed that the immunostimulatory TNFSF9/41BBL was significantly reduced in NFE2L1 knockdown hepatocarcinoma HepG2 cells, and this suggests that 41BBL may be an oxidative stress-responsive immune checkpoint. The results of the promoter activity experiment showed that NFE2L1 can promote 41BBL gene transcription activation through the ARE element in the promoter region. In addition, cell biology experiments have found that overexpression of 41BBL can inhibit cell proliferation and promote senescence. Importantly, reactive oxygen species in cells significantly increased after overexpression of 41BBL, whereas NFE2L1 was inhibited, indicating that 41BBL has the effect of feedback regulating oxidative stress in cells. In conclusion, in this study, the transcriptional activation effect of NFE2L1 on 41BBL and the feedback inhibition relationship of 41BBL on NFE2L1 was clarified. The NFE2L1/41BBL axis might be an important pathway that mediates the crosstalk between oxidative stress and the tumor immune response.