T cells (green and red) surrounding a cancer cell (blue, center). Image credit: Alex Ritter, Jennifer Lippincott Schwartz and Gillian Griffiths, National Institutes of Health via flickr (Public domain).
Immunotherapies are treatments that have revolutionized cancer care by helping a patient’s own immune system find and destroy cancer cells. Unfortunately, less than half of treated patients respond to these therapies, with tumors often learning to escape detection by the immune system.
One way that cancer cells can evade the immune system is by preventing themselves from producing mutant proteins. By stopping these proteins from reaching the cell surface, the abnormal cell is less likely to be detected and killed by the immune system. One way cancer cells accomplish this is by destroying the RNA templates needed to make the proteins through a process called ‘nonsense-mediated decay’. Therefore, developing a therapy that can stop nonsense-mediated decay could help the immune system find and kill more tumor cells.
Cook et al. screened thousands of drugs with the aim of finding one that blocks nonsense-mediated decay. Although one drug was identified that could inhibit a gene called SMG1 (which is known to activate nonsense-mediated decay), it was too toxic in animal models to be considered as a therapy. Therefore, Cook et al. developed a new drug targeting this gene that slowed tumor growth in mice without showing the same toxicity. Treating human cancer cells with the drug also increased the number of mutant proteins on the cell surface displayed to the immune system, suggesting the drug has the potential to prevent nonsense-mediated decay in humans.
The findings suggest that the drug developed by Cook et al. may make it easier for the immune system to identify and destroy certain cancer cells. This might also be relevant for other conditions involving nonsense-mediated decay, such as cystic fibrosis, Alport’s disease, and Duchenne muscular dystrophy. If further studies confirm that the drug is safe and effective in humans, it could be used alongside cancer immunotherapies to improve patient response rates.
