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PDL1 Regulation by p53 via miR-34
BACKGROUND: Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non–small cell lung cancer (NSCLC), the regulation of PDL1 expression is poorly understood. Here, we show that PDL1 is regulated by p53 via miR-34. METHODS: p53 wild-type and p53-deficient cell lines (p53(–/...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862407/ https://www.ncbi.nlm.nih.gov/pubmed/26577528 http://dx.doi.org/10.1093/jnci/djv303 |
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author | Cortez, Maria Angelica Ivan, Cristina Valdecanas, David Wang, Xiaohong Peltier, Heidi J. Ye, Yuping Araujo, Luiz Carbone, David P. Shilo, Konstantin Giri, Dipak K Kelnar, Kevin Martin, Desiree Komaki, Ritsuko Gomez, Daniel R. Krishnan, Sunil Calin, George A. Bader, Andreas G. Welsh, James W. |
author_facet | Cortez, Maria Angelica Ivan, Cristina Valdecanas, David Wang, Xiaohong Peltier, Heidi J. Ye, Yuping Araujo, Luiz Carbone, David P. Shilo, Konstantin Giri, Dipak K Kelnar, Kevin Martin, Desiree Komaki, Ritsuko Gomez, Daniel R. Krishnan, Sunil Calin, George A. Bader, Andreas G. Welsh, James W. |
author_sort | Cortez, Maria Angelica |
collection | PubMed |
description | BACKGROUND: Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non–small cell lung cancer (NSCLC), the regulation of PDL1 expression is poorly understood. Here, we show that PDL1 is regulated by p53 via miR-34. METHODS: p53 wild-type and p53-deficient cell lines (p53(–/–) and p53(+/+) HCT116, p53-inducible H1299, and p53-knockdown H460) were used to determine if p53 regulates PDL1 via miR-34. PDL1 and miR-34a expression were analyzed in samples from patients with NSCLC and mutated p53 vs wild-type p53 tumors from The Cancer Genome Atlas for Lung Adenocarcinoma (TCGA LUAD). We confirmed that PDL1 is a direct target of miR-34 with western blotting and luciferase assays and used a p53(R172HΔ)g/+K-ras(LA1/+) syngeneic mouse model (n = 12) to deliver miR-34a–loaded liposomes (MRX34) plus radiotherapy (XRT) and assessed PDL1 expression and tumor-infiltrating lymphocytes (TILs). A two-sided t test was applied to compare the mean between different treatments. RESULTS: We found that p53 regulates PDL1 via miR-34, which directly binds to the PDL1 3’ untranslated region in models of NSCLC (fold-change luciferase activity to control group, mean for miR-34a = 0.50, SD = 0.2, P < .001; mean for miR-34b = 0.52, SD = 0.2, P = .006; and mean for miR-34c = 0.59, SD = 0.14, and P = .006). Therapeutic delivery of MRX34, currently the subject of a phase I clinical trial, promoted TILs (mean of CD8 expression percentage of control group = 22.5%, SD = 1.9%; mean of CD8 expression percentage of MRX34 = 30.1%, SD = 3.7%, P = .016, n = 4) and reduced CD8(+)PD1(+) cells in vivo (mean of CD8/PD1 expression percentage of control group = 40.2%, SD = 6.2%; mean of CD8/PD1 expression percentage of MRX34 = 20.3%, SD = 5.1%, P = .001, n = 4). Further, MRX34 plus XRT increased CD8(+) cell numbers more than either therapy alone (mean of CD8 expression percentage of MRX34 plus XRT to control group = 44.2%, SD = 8.7%, P = .004, n = 4). Finally, miR-34a delivery reduced the numbers of radiation-induced macrophages (mean of F4-80 expression percentage of control group = 52.4%, SD = 1.7%; mean of F4-80 expression percentage of MRX34 = 40.1%, SD = 3.5%, P = .008, n = 4) and T-regulatory cells. CONCLUSIONS: We identified a novel mechanism by which tumor immune evasion is regulated by p53/miR-34/PDL1 axis. Our results suggest that delivery of miRNAs with standard therapies, such as XRT, may represent a novel therapeutic approach for lung cancer. |
format | Online Article Text |
id | pubmed-4862407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-48624072016-05-11 PDL1 Regulation by p53 via miR-34 Cortez, Maria Angelica Ivan, Cristina Valdecanas, David Wang, Xiaohong Peltier, Heidi J. Ye, Yuping Araujo, Luiz Carbone, David P. Shilo, Konstantin Giri, Dipak K Kelnar, Kevin Martin, Desiree Komaki, Ritsuko Gomez, Daniel R. Krishnan, Sunil Calin, George A. Bader, Andreas G. Welsh, James W. J Natl Cancer Inst Article BACKGROUND: Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non–small cell lung cancer (NSCLC), the regulation of PDL1 expression is poorly understood. Here, we show that PDL1 is regulated by p53 via miR-34. METHODS: p53 wild-type and p53-deficient cell lines (p53(–/–) and p53(+/+) HCT116, p53-inducible H1299, and p53-knockdown H460) were used to determine if p53 regulates PDL1 via miR-34. PDL1 and miR-34a expression were analyzed in samples from patients with NSCLC and mutated p53 vs wild-type p53 tumors from The Cancer Genome Atlas for Lung Adenocarcinoma (TCGA LUAD). We confirmed that PDL1 is a direct target of miR-34 with western blotting and luciferase assays and used a p53(R172HΔ)g/+K-ras(LA1/+) syngeneic mouse model (n = 12) to deliver miR-34a–loaded liposomes (MRX34) plus radiotherapy (XRT) and assessed PDL1 expression and tumor-infiltrating lymphocytes (TILs). A two-sided t test was applied to compare the mean between different treatments. RESULTS: We found that p53 regulates PDL1 via miR-34, which directly binds to the PDL1 3’ untranslated region in models of NSCLC (fold-change luciferase activity to control group, mean for miR-34a = 0.50, SD = 0.2, P < .001; mean for miR-34b = 0.52, SD = 0.2, P = .006; and mean for miR-34c = 0.59, SD = 0.14, and P = .006). Therapeutic delivery of MRX34, currently the subject of a phase I clinical trial, promoted TILs (mean of CD8 expression percentage of control group = 22.5%, SD = 1.9%; mean of CD8 expression percentage of MRX34 = 30.1%, SD = 3.7%, P = .016, n = 4) and reduced CD8(+)PD1(+) cells in vivo (mean of CD8/PD1 expression percentage of control group = 40.2%, SD = 6.2%; mean of CD8/PD1 expression percentage of MRX34 = 20.3%, SD = 5.1%, P = .001, n = 4). Further, MRX34 plus XRT increased CD8(+) cell numbers more than either therapy alone (mean of CD8 expression percentage of MRX34 plus XRT to control group = 44.2%, SD = 8.7%, P = .004, n = 4). Finally, miR-34a delivery reduced the numbers of radiation-induced macrophages (mean of F4-80 expression percentage of control group = 52.4%, SD = 1.7%; mean of F4-80 expression percentage of MRX34 = 40.1%, SD = 3.5%, P = .008, n = 4) and T-regulatory cells. CONCLUSIONS: We identified a novel mechanism by which tumor immune evasion is regulated by p53/miR-34/PDL1 axis. Our results suggest that delivery of miRNAs with standard therapies, such as XRT, may represent a novel therapeutic approach for lung cancer. Oxford University Press 2015-11-17 /pmc/articles/PMC4862407/ /pubmed/26577528 http://dx.doi.org/10.1093/jnci/djv303 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Article Cortez, Maria Angelica Ivan, Cristina Valdecanas, David Wang, Xiaohong Peltier, Heidi J. Ye, Yuping Araujo, Luiz Carbone, David P. Shilo, Konstantin Giri, Dipak K Kelnar, Kevin Martin, Desiree Komaki, Ritsuko Gomez, Daniel R. Krishnan, Sunil Calin, George A. Bader, Andreas G. Welsh, James W. PDL1 Regulation by p53 via miR-34 |
title | PDL1 Regulation by p53 via miR-34 |
title_full | PDL1 Regulation by p53 via miR-34 |
title_fullStr | PDL1 Regulation by p53 via miR-34 |
title_full_unstemmed | PDL1 Regulation by p53 via miR-34 |
title_short | PDL1 Regulation by p53 via miR-34 |
title_sort | pdl1 regulation by p53 via mir-34 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862407/ https://www.ncbi.nlm.nih.gov/pubmed/26577528 http://dx.doi.org/10.1093/jnci/djv303 |
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