PDL1 Regulation by p53 via miR-34

TP53, also known as p53, is one of the most commonly mutated genes in cancer (1). It is critical in regulating cell division, apoptosis, senescence, and DNA damage and repair (2–4). p53 is also important for modulating the immune response (5–9). However, whether p53 is involved in tumor immune evasion is poorly understood. This topic is particularly relevant for several reasons, among them evidence linking microRNAs (miRNAs), p53, and adaptive and innate immunity (6,10). For instance, several p53-regulated miRNAs have been implicated in adaptive and innate immunity, including the miR-17~92 cluster (11), miR-145 (12), and let-7 (13). Importantly, p53 can regulate tumor cell recognition by natural killer (NK) cells via the p53-regulated miRNA miR-34a (10). We recently showed that the miR-200 family, another miRNA family regulated by p53 (14), directly regulates PDL1 (programmed death 1 ligand 1; also known as B7-H1 or CD274) (15). PDL1 is overexpressed in many human cancers, including non–small cell lung cancer (NSCLC) (16–18), promoting T-cell tolerance and escape host immunity (19). Early clinical trials using monoclonal antibodies that block the PD1/PDL1 interaction have shown promise in some patients with advanced cancer (20,21). Here, we investigated the potential role of p53 in regulating PDL1 expression in NSCLC. We found that p53 regulates PDL1 via miR-34 by using a series of experiments involving lung cancer cell lines, miRNA target-predicting databases, and tissue samples from patients with NSCLC. Using a syngeneic mouse model of lung cancer, we demonstrated that MRX34, a liposomal formulation complexed with miR-34a mimics that is currently the subject of a phase I clinical cancer trial (22–24), alone or in combination with radiotherapy (XRT), reduced PDL1 expression in the tumor and antagonized T-cell exhaustion.