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

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

  • Exp Mol Med. 2021 Sep;53(9):1366-1378. doi: 10.1038/s12276-021-00670-3.
Fu Du 1,  Xin Qi 1 2,  Aotong Zhang 1,  Fanfan Sui 1,  Xuemin Wang 3,  Christopher G Proud 3 4,  Cunzhi Lin 5,  Xinglong Fan 6,  Jing Li 7 8 9
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China.
  • 2 Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, People's Republic of China.
  • 3 South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia.
  • 4 School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia.
  • 5 Department of Respiratory & Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266555, China.
  • 6 Department of Thoracic Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, China.
  • 7 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China. [email protected].
  • 8 Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, People's Republic of China. [email protected].
  • 9 Open Studio for Drug Research on Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, People's Republic of China. [email protected].
PMID: 34548615 DOI: 10.1038/s12276-021-00670-3
Abstract

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.

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