PDL1 Regulation by p53 via miR-34

By M. Cortez, C. Ivan, D. Valdecanas, Xiaohong Wang, Heidi J. Peltier, Yuping Ye, L. Araújo, D. Carbone, K. Shilo, D. Giri and 8 more. Journal of the National Cancer Institute, 2015

653 citations recorded by the source corpus.

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 p53R172HΔg/+K-rasLA1/+ 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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/13663e98fc192167856c3c5b9b075a04ae1169ef

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Citations in the corpus

Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma (2016, result): “Recent studies had shown TP53 or KRAS mutant NSCLC expressed higher levels of PD-L1 protein compared with corresponding wild-type tumors (16, 17).”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “In NSCLC, wild-type P53-induced miR-34 directly binds to the 3 ′ -UTR of PD-L1 to inhibit PD-L1 mRNA expression, the therapeutic delivery of miR-34a combined with radiotherapy can increase T cell infiltration and inhibit tumor growth [243].”
Mechanisms controlling PD-L1 expression in cancer (2019, background): “Strikingly, both miR-200 and miR-34a are transcriptionally upregulated by p53 (Chang et al., 2011; Cortez et al., 2016).”
PD-1/PD-L1 pathway: current researches in cancer. (2020, background): “A recent study demonstrated the synergy between miR-34a delivery and radiation therapy, which induces an immune response to the tumor through targeting PD-L1, leading to an increase in tumor infiltration by CD8+ cells and a significant reduction in tumor volume compared with either treatment alone [”