Abstract
Abstract Background Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non-small cell lung cancer (NSCLC), little is known of how PDL1 expression is regulated. We previously found that miR-200s directly regulate PDL1; here we show that PDL1 is regulated by miR-34a and p53. Methods We confirmed that PDL1 is a direct target of miR-34a with western blotting and luciferase assays. We then used in vitro models (p53-/- and p53+/+ HCT116 cells, p53-inducible H1299 cells, and p53-knockdown H460 cells) to determine if p53 regulates PDL1 via miR-34a. Next, we analyzed p53, PDL1, and miR-34a expression in formalin-fixed paraffin-embedded specimens from patients with NSCLC. Finally, we used a p53R172HΔg/+K-rasLA1/+ syngeneic mouse model to deliver miR-34a-loaded liposomes (MRX34) plus radiotherapy and assessed PDL1 expression and tumor-infiltrating lymphocytes (TILs). Results We found that p53 regulates PDL1 via miR-34a, which directly binds to the PDL1 3′ untranslated region, in NSCLC. Delivery of MRX34 (previously tested in a phase I clinical trial) promoted CD8+ TILs and reduced CD8+PD1+ cells in vivo. Further, MRX34 plus radiotherapy increased CD8+ cell numbers more than either therapy alone. Finally, we showed that miR-34a delivery reduced the numbers of radiation-induced macrophages and T regulatory cells. Conclusions We identified a novel mechanism by which tumor immune evasion is regulated by p53 and miR-34a via PDL1. Our results suggest that delivery of miR-34a combined with standard therapies, such as radiotherapy, may represent a novel therapeutic approach for lung cancer. Citation Format: Maria A. Cortez, David Valdecanas, Xiaohong Wang, Cristina Ivan, Heidi Peltier, Huiping Ye, Luiz Araujo, David Carbone, Dipak K. Giri, Ritsuko Komaki, Sunil Krishnan, Ferdinandos Skoulidis, John Heymach, George Calin, Andreas G. Bader, James W. Welsh. p53 regulation of PDL1 is mediated through miR-34a. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2875. doi:10.1158/1538-7445.AM2015-2875
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