During the 2015 American Association for Cancer Research (AACR) Annual Meeting in Philadelphia, researchers from The University of Texas MD Anderson Cancer Center presented their findings on the regulation of the protein PD-L1 by the tumor suppressor gene p53 and its consequences on the growth of non-small cell lung cancer.
Programmed death-ligand 1 (PD-L1) is a protein known to suppress the body’s immune system by preventing the activation of immune T-cells. PD-L1 can be found on the surface of tumor cells, allowing them to evade the immune system. Promising therapeutic strategies based on PD-L1 blockade have been developed for several cancers, including lung cancer, which is the major cause of cancer deaths in the United States and worldwide. PD-L1 based approaches, however, are not effective in all patients.“Although clinical studies have shown promise for targeting PD-1/PD-L1 signaling in non-small cell lung cancer, little is known about how PD-L1 expression is regulated,” noted Dr. James Welsh at MD Anderson in a news release.
The tumor suppressor gene p53 is known to regulate PD-L1 expression. Mutations in the p53 gene have been linked with the development of several cancers as these mutations usually result in the promotion of tumor growth. Researchers now found that a small non-coding RNA molecule called microRNA-34a (miR-34a), which is commonly found in the lung and is often under-expressed or absent in tumors, is regulated by p53. “We identified a novel mechanism by which p53 regulates PD-L1 and tumor immune evasion through control of miR-34a expression,” said Dr. Welsh.
Using mice models, the research team found that an experimental drug called MRX34, that mimics the tumor suppressing properties of miR-34, is able to increase the number of specific CD8 immune T cells when combined with radiotherapy. MD Anderson is currently conducting a clinical trial to evaluate MRX34 efficacy.
The team believes that a better understanding of the mechanism underlying PD-L1 regulation pathways may offer new therapeutic strategies for cancer patients. “Our results suggest that miR-34a delivery combined with standard therapies, such as radiotherapy, may represent a novel therapeutic approach for lung cancer,” said Dr. Maria Angelica Cortez at MD Anderson.