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.

doi:10.1093/jnci/djv303

Cited by 685Cancer Immunotherapy and BiomarkersMicroRNA in disease regulationCancer-related Molecular Pathways

PDL1 Regulation by p53 via miR-34

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Cortez, Maria Angelica, Ivan, Cristina, Valdecanas, David, Wang, Xiaohong, Peltier, Heidi J., Ye, Yuping, Araujo, Luiz, Carbone, David P. +10 more·2016·JNCI: Journal of the National Cancer Institute

DOI 10.1093/jnci/djv303PMC PMC4862407

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Abstract

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.

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Activating wild-type proteins can increase IFNγ signaling and sensitize tumors to immune checkpoint inhibitors, whereas corresponding mutant proteins can reduce the efficacy of immune checkpoint inhibitors.
“On the other hand, activating wild-type proteins can increase IFNγ signaling and sensitize tumors to immune checkpoint inhibitors, whereas corresponding mutant proteins can reduce the efficacy of immune checkpoint inhibitors.612–614”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [612]
Some missense mutant proteins can lose the transcriptional effects of wild-type genes, such as keeping PDL1 expression low, making cancer cells more susceptible to cytotoxic T cells and NK cells, limiting the immune system's ability to attack cancer cells.
“Some missense mutant proteins can lose the transcriptional effects of wild-type genes, such as keeping PDL1 expression levels low, thereby making cancer cells more susceptible to cytotoxic T cells and NK cells, limiting the immune system’s ability to attack cancer cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [612]
The status of genes can influence tumor cells through the impact of wild-type gene loss and through their effects on the tumor immune microenvironment.
“In brief, the status of genes can influence tumor cells not only through the impact of wild-type gene loss but also through their effects on the TIME.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [612]

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Wang, Y., Sun, Q., Mu, N., Sun, X., Wang, Y., Fan, S., Su, L., & Liu, X. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00612-y · Cited by 124 · see citing works
Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology
Bristow, R. G., Alexander, B. M., Baumann, M. A., Bratman, S. V., Brown, J. M., Camphausen, K. A., Choyke, P. L., Citrin, D. E., Contessa, J. N., Dicker, A. P., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30096-2 · Cited by 121 · see citing works

Abstract 2875: p53 regulation of PDL1 is mediated through miR-34a
Cortez, M. A., Valdecanas, D. R., Wang, X., Ivan, C., Peltier, H. J., Ye, H., Araujo, L. H., Carbone, D. P., Giri, D. K., Komaki, R. U., et al. (2015) · Cancer Research · doi:10.1158/1538-7445.am2015-2875 · Cited by 5 · see citing works
Self-citation
The correlation of PD-L1 and microRNA-34a and their clinical implications in human non-small cell lung cancer.
Hong, J. H., Roh, K. S., Suh, S., Lee, S., Byun, J. H., Jung, C. K., Park, J. K., & Kang, J. H. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.34.15_suppl.e23277 · Cited by 3 · see citing works
MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC
Xie, W., Liang, L., Wu, K.-G., Wang, L.-X., He, X., Song, C., Wang, Y., & Li, Y. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000488634 · Cited by 80 · see citing works
Abstract 4392: Tumor suppressor miR-339-5p regulates PD-L1 expression in lung cancer
Heymach, R., Diao, L., Byers, L. A., Nilsson, M. B., Wang, J., & Cortez, M. A. (2014) · Cancer Research · doi:10.1158/1538-7445.am2014-4392 · Cited by 2 · see citing works
Self-citation
MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer
Garofalo, M., Jeon, Y.-J., Nuovo, G. J., Middleton, J. D., Secchiero, P., Joshi, P., Alder, H., Nazaryan, N., Leva, G. D., Romano, G., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067581 · Cited by 120 · see citing works

Authors: Cortez, M. A., Ivan, C., Valdecanas, D., Wang, X., Peltier, H. J., Ye, Y., Araujo, L., Carbone, D. P., Shilo, K., Giri, D. K., Kelnar, K., Martin, D., Komaki, R., Gomez, D. R., Krishnan, S., Calin, G. A., Bader, A. G., & Welsh, J. W.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
Corresponding author: Welsh, James W.
ORCID: Ivan, Cristina
Wang, Xiaohong
Araujo, Luiz
Carbone, David P.
Shilo, Konstantin
Gomez, Daniel R.
Bader, Andreas G.
Welsh, James W.
Venue: JNCI: Journal of the National Cancer Institute
Publisher: Oxford University Press (OUP)
Published: 2015-11-17
Volume: 108
Issue: 1
ISSN: 0027-8874 (ISSN-L)
1460-2105
DOI: 10.1093/jnci/djv303
PMC: PMC4862407
OpenAlex: W2173135538
Cited by: 683
References: 57
Citations by year: 2026: 42 · 2025: 53 · 2024: 72 · 2023: 66 · 2022: 72 · 2021: 94 · 2020: 86 · 2019: 61 · 2018: 62 · 2017: 50 · 2016: 24 · 2012: 1
FWCI: 19.80
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: JNCI Journal of the National Cancer Institute (publishedVersion)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Funders: U.S. Department of Defense (W81XWH0610303, W81XWH, W81XWH-07-1-03060)
Cancer Prevention and Research Institute of Texas (CA016672)
Doctors Cancer Foundation
Lung Cancer Research Foundation
National Institutes of Health (UH2TR000943, W81XWH, CA- 016672, 1UH2TR00943-01)
University of Texas MD Anderson Cancer Center ((CA016672), grant CA016672)
National Cancer Institute (Grant CA016672, CA 016672, CA016672 to, 1UH2TR00943-01, R01CA182905, P30CA016672)
National Center for Advancing Translational Sciences (1UH2TR00943-01)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: PD-L1, p53, miR-34, non-small cell lung cancer, lung adenocarcinoma, miR-34a, miR-34b, miR-34c, 3' untranslated region, tumor-infiltrating lymphocytes, radiotherapy, immune checkpoint, TP53 mutation
MeSH terms: Adenocarcinoma of Lung, Adenocarcinoma, Animals, Carcinoma, Non-Small-Cell Lung, Liposomes, Lung Neoplasms, Neoplasms, Experimental, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, CD8 Antigens, MicroRNAs, Cell Line, Tumor, Cell Proliferation, Mice, B7-H1 Antigen

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