MicroRNAs May Be Key to Better Immunotherapy for Mesothelioma

Australian scientists say it may be possible to artificially reduce the levels of a protein that helps mesothelioma tumors hide from the immune system.

The new research published in the Journal of Thoracic Oncology could open the door to more effective immunotherapy treatments for pleural mesothelioma.

The Importance of PD-L1 Expression

A cell surface protein called PD-L1 is key to the effectiveness of several new immunotherapy drugs including Keytruda (pembrolizumab), Opdivo (nivolumab), and avelumab.

An estimated 40 percent of mesothelioma tumors overexpress this protein, which is part of the process that allows several different kinds of cancers to escape detection and attack by the immune system.

Now, a new study conducted at the Asbestos Diseases Research Institute at the University of Sydney has revealed more about the mechanisms behind PD-L1 expression in malignant mesothelioma. The results suggest that it may be possible to downregulate this tumor-protecting protein from the inside out.

MicroRNA Expression and Malignant Mesothelioma

MicroRNAs are short, single-stranded RNA molecules that regulate gene expression, which, in turn, governs all kinds of cellular processes.

Among 72 test subjects  with malignant pleural mesothelioma, the Australian team found that 18 (25%) tested positive for PD-L1 overexpression. The PD-L1-positive mesothelioma patients showed key differences in the action of certain microRNAs.

“In the same patient series, PD-L1 expression was also associated with downregulation of microRNAs previously shown to have tumour suppressor activity in malignant pleural mesothelioma,” writes Steven C. Kao, the lead author on the paper.

When the researchers manipulated these microRNAs by transfecting mesothelioma cell lines with artificial microRNAs or “mimics”, they found that they were able to downregulate the expression of the PD-L1 protein.

PD-L1 Impact on Mesothelioma Survival

The new findings are significant because mesothelioma patients who overexpress PD-L1 have poorer outcomes than patients who don’t.

The Australian researchers found that test subjects whose mesothelioma tumors tested positive for PD-L1 were more likely to have either the biphasic or sarcomatoid subtype of mesothelioma and tended to experience shorter survival.

The median overall survival of the PD-L1-expressing mesothelioma patients was just 4 months, compared to 9.2 months for the mesothelioma patients with negative PD-L1 staining.

“Together, these data suggest that tumour suppressor microRNAs contribute to the regulation of PD-L1 expression in malignant pleural mesothelioma,” writes Dr. Kao.

Source:

Kao, SC, et al, “Tumour suppressor microRNAs contribute to the regulation of PD-L1 expression in malignant pleural mesothelioma”, June 16, 2017, Journal of Thoracic Oncology, Epub ahead of print