MRTF-A-NF-κB/p65 axis-mediated PDL1 transcription and expression contributes to immune evasion of non-small-cell lung cancer via TGF-β.

PD-L1 is abnormally regulated in many cancers and is critical for immune escape. Fully understanding the regulation of PD-L1 expression is vital for improving the clinical efficacy of relevant anticancer agents. TGF-β plays an important role in the low reactivity of PD-1/PD-L1 antibody immunotherapy. However, it is not very clear whether and how TGF-β affects PD-L1 expression. In the present study, we show that TGF-β upregulates the expression of the transcriptional coactivator MRTF-A in non-small-cell lung cancer cells, which subsequently interacts with NF-κB/p65 rather than SRF to facilitate the binding of NF-κB/p65 to the PDL1 promoter, thereby activating the transcription and expression of PD-L1. This leads to the immune escape of NSCLC cells. This process is dependent on the activation of the TGF-β signaling pathway. In vivo, inhibition of MRTF-A effectively suppresses the growth of lung tumor syngrafts with enrichment of NK and T cells in tumor tissue. Our study defines a new signaling pathway that regulates the transcription and expression of PD-L1 upon TGF-β treatment, which may have a significant impact on research into the application of immunotherapy in treating lung cancer. Better understanding how a critical protein to allow cancer cells to escape immune system may aid in development of improved immunotherapies for lung cancer. The membrane protein PD-L1, expressed on tumor cells, helps them to evade the immune surveillance; existing treatments that block PD-L1 have very low efficacy for some patient partly due to re-expression of PD-L1. Jing Li at Ocean University of China in Qingdao and co-workers found that TGF-β up-regulated in tumor microenvironment boosts PD-L1 transcription and expression in an unusual way, namely, via MRTF-A-NF-κB/p65 axis. Blocking MRTF-A in a mouse model remarkably increased levels of immune cells targeting the tumor and slowed lung tumor growth. These results illuminate the mechanism of immune escape in lung cancers upon TGF-β, which may contribute to develop new treatment to synergize PD-L1 antibody therapy.