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.

PD-L1 在许多癌症中受到异常调节，对免疫逃逸至关重要。充分了解PD-L1表达的调控对于提高相关抗癌药物的临床疗效至关重要。TGF-β在PD-1/PD-L1抗体免疫治疗的低反应性中起重要作用。然而，尚不清楚 TGF-β 是否以及如何影响 PD-L1 表达。在本研究中，我们表明 TGF-β 上调非小细胞肺癌细胞中转录共激活因子 MRTF-A 的表达，随后与 NF-κB/p65 而不是 SRF 相互作用以促进 NF- κB/p65 到PDL1启动子，从而激活 PD-L1 的转录和表达。这导致NSCLC细胞的免疫逃逸。这个过程依赖于 TGF-β 信号通路的激活。在体内，抑制MRTF -A 可有效抑制肺肿瘤移植物的生长，并在肿瘤组织中富集 NK 和 T 细胞。我们的研究定义了一种新的信号通路，在TGF-β治疗后调节PD-L1的转录和表达，这可能对免疫疗法在肺癌治疗中的应用研究产生重大影响。