Some patients receiving immune checkpoint therapy develop mutations that impair antigen presentation, resulting in therapeutic resistance that renders the treatment useless. To combat this issue, scientists have been working to identify the role that enzymes play in cancer, as they are critical parts of the immune system.
One of these enzymes, adenosine deaminase associated with RNA1 (ADAR1), is a stem cell enzyme that is responsible for marking human virus-like genes in order to avoid confusing them with viruses. During some cancer cases, ADAR1 gets hijacked by malignant cells, thereby leaving it unable to perform its normal functions.
In a new study, published in Nature, researchers at Bar-Ilan University and Harvard Medical School have discovered that by inhibiting the normal functions of ADAR1, the immune system becomes more responsive and vigorous, thereby increasing its ability to fight cancerous cells.
"We found that if the mechanism is blocked, the immune system is much more sensitive. When the mechanism is deactivated, the immune system becomes much more aggressive against the tumor cells," remarked Erez Levanon, PhD, Professor at The Mina and Everard Goodman Faculty of Life Sciences at Bar-IIan University in Israel.
The investigators discovered that once ADAR1 is blocked, A-to-I—adenosine to inosine—editing of interferon-inducible RNA species is reduced, resulting in double-stranded RNA ligand sensing by innate immune sensors known as PKR and MDA5. A-to-I editing occurs to generate RNA and protein diversity. This ultimately leads to growth inhibition and tumor inflammation. In addition, ADAR1 inhibition relieves resistance to anti–PD-1 checkpoint therapy due to inactivation of antigen presentation by tumor cells. The researchers found that blocking ADAR1 is particularly effective in lung cancer and melanoma.
Further research needs to be conducted on the efficacy of ADAR1 inhibition therapy, but hopefully, inhibiting ADAR1 to allow the immune system to fight cancer will enable a more effective treatment in the future.
For More Information
Ishizuka JJ, Manguso RT, Cheruiyot CK, et al (2019). Loss of ADAR1 in tumors overcomes resistance to immune checkpoint blockade. Nature, 563(7737):43-48. DOI:10.1038/s41586-018-0768-9
Image courtesy of Jawahar Swaminathan