Inhibition of yes-associated protein down-regulates PD-L1 (CD274) expression in human malignant pleural mesothelioma

Our plain-English summary of Inhibition of yes-associated protein down-regulates PD-L1 (CD274) expression in human malignant pleural mesothelioma, by P.C. Hsu, J. Miao, Y.C. Wang, et al (Journal of Cellular and Molecular Medicine, 2018).

The study

• Authors: P.C. Hsu, J. Miao, Y.C. Wang, W.Q. Zhang, Y.L. Yang, C.W. Wang, C.T. Yang, Z. Huang, J. You, Z. Xu, D.M. Jablons, L. You
• Journal: Journal of Cellular and Molecular Medicine
• Published: 2018;22(6):3139-3148
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Although tumour PD-L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD-L1 axis in various cancers, the regulation of PD-L1 (CD274) expression is unclear. Yes-associated protein (YAP), an important oncogenic protein in Hippo signalling pathway, reportedly promotes cancer development. We investigated whether inhibition of YAP down-regulates PD-L1 (CD274) in human malignant pleural mesothelioma (MPM). Western blotting showed that 2 human MPM cell lines (H2052 and 211H) had increased PD-L1 protein expression compared to H290, MS-1 and H28 cells. In H2052 and 211H cells, PD-L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD-L1 protein and mRNA expression. Forced overexpression of the YAP gene increased PD-L1 protein expression in H2452 cells. Chromatin immunoprecipitation (ChIP) assay showed the precipitation of PD-L1 enhancer region encompassing 2 putative YAP-TEAD-binding sites in H2052 cells. We found that, in human MPM tissue microarray samples, YAP and PD-L1 concurrently expressed in immunohistochemistry stain (n = 70, P < .05, chi-square). We conclude that PD-L1 is correlated with YAP expression, and inhibition of YAP down-regulates PD-L1 expression in human MPM. Further study of how YAP regulates PD-L1 in MPM is warranted.

© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

In plain English

This laboratory study asked whether a protein called YAP controls the level of PD-L1, a molecule targeted by some immunotherapy drugs, in malignant pleural mesothelioma. It did not examine asbestos exposure. The authors used six mesothelioma cell lines, a normal mesothelial cell line, a lung cancer cell line, and tumour tissue from 70 patients whose pleural mesothelioma had been surgically removed. Two lines, H2052 and 211H, had higher PD-L1, including 6-fold higher PD-L1 mRNA than several others. Knocking down YAP with siRNA, or treating cells with the YAP inhibitor verteporfin, reduced PD-L1 in these two lines. Adding extra YAP raised it again. A binding test suggested YAP attaches to a control region of the PD-L1 gene. In the patient tissue, moderate to strong PD-L1 staining went together with moderate to strong nuclear YAP staining (p less than 0.05), and the authors described 31.4% (22/70) of samples as showing co-expression. The authors concluded YAP may help mesothelioma cells escape immune attack by raising PD-L1. They noted the samples were 10-20 years old, with too little tissue left for further testing.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human cell lines (gene knockdown, overexpression, drug treatment, chromatin immunoprecipitation) plus immunohistochemistry on a tumour tissue microarray
• Who was studied: Human mesothelioma cell lines H2052, 211H, H28, H2452, H290 and MS-1; normal mesothelial cell line LP-9; lung cancer cell line A549; and primary malignant pleural mesothelioma tissue with adjacent normal pleura from 70 patients whose tumours were surgically resected (samples obtained under a University of California, San Francisco protocol)
• Exposure: No asbestos or other environmental exposure was studied. The experimental interventions were reducing YAP with small interfering RNA (siRNA), forcing extra YAP with a plasmid, and treating cells with the YAP inhibitor verteporfin at 1.0 and 2.0 micromolar
• Main results:
  • Of the mesothelioma cell lines, H2052 and 211H had increased PD-L1 protein. Their PD-L1 mRNA was 6-fold higher than in LP-9, H290, MS-1, H28 and H2452 cells (P < .001)
  • In H2052 and 211H cells, reducing YAP with siRNA decreased PD-L1 at both the protein and mRNA level
  • Forcing extra YAP increased PD-L1 protein in H2452 and A549 cells, which have low YAP and low PD-L1. In H2052 and 211H cells, it restored PD-L1 after YAP knockdown
  • Chromatin immunoprecipitation in H2052 cells suggested that YAP binds to an enhancer region of the PD-L1 gene
  • In H2052 and 211H cells, the YAP inhibitor verteporfin at 1.0 and 2.0 micromolar decreased PD-L1 protein and significantly decreased PD-L1 mRNA
  • In the 70 mesothelioma tissue samples, PD-L1 staining was negative in 28.6%, weak in 34.2% and moderate to strong in 37.2%. YAP and PD-L1 staining were negative in normal pleural tissue
  • In the 70 tissue samples, nuclear YAP staining was negative in 15.7%, weak in 30.0% and moderate to strong in 54.3%
  • In the 70 tissue samples, moderate to strong PD-L1 staining was concurrent with moderate to strong nuclear YAP staining (P < .05, chi-square). The authors described 31.4% (22/70) of samples as showing YAP and PD-L1 co-expression, without stating which staining grades they counted
• The authors' conclusion: The authors concluded that inhibiting YAP down-regulates PD-L1 in human malignant pleural mesothelioma. They suggested that YAP may help mesothelioma cells escape the anticancer immune response by increasing tumour PD-L1, and they called for further study of how YAP regulates PD-L1
• Limitations the authors state:
  • The patient samples had first been studied 10-20 years earlier, and not enough tissue was left for further molecular study of YAP and PD-L1
  • Some tumours with weak nuclear YAP staining still expressed PD-L1 (5.7%, 4/70), and the authors noted that factors other than YAP may also regulate PD-L1

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Mesothelioma, Biomarker, Immunotherapy, Immunohistochemistry.

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