Researchers describe how ammonia dysregulates activity of T cells

Recent studies from the University of Michigan Rogel Cancer Center show that when tumours contain high levels of ammonia, mice used to simulate colorectal cancer show immunotherapy resistance and have fewer T cells. The body’s capacity to fight tumours depends on T lymphocytes, but ammonia inhibits their growth and function.
The study’s findings were disseminated in the journal Cell Metabolism.

“We identified the mechanism of how ammonia dysregulates T cell function and showed that reducing ammonia levels using FDA-approved drugs for hyperammonemia can reduce tumor size in several different models including metastatic colorectal cancer,” says Hannah Bell, Ph.D., a postdoctoral fellow in cancer biology and author on this paper, adding, “Use of this drug also synergizes with immunotherapy. If you treat the mice with immunotherapy when you also treat them with this ammonia reducing agent, you’re able to sensitize the tumors to treatment.”

“Most colorectal cancers are insensitive to immune therapies,” adds Yatrik Shah, Ph.D., Horace W. Davenport Collegiate Professor of Physiology and first author of the study, adding, “We’ve found that one of the mechanisms that leads to this resistance is likely the high level of ammonia that accumulates in the microenvironment.”

According to Bell, there are few therapeutic measures that can reawaken therapy sensitivity even though there are several elements that lead to immunotherapy resistance. ” Our research demonstrates that this is a relatively safe and FDA-approved technique that may be used in conjunction with immunotherapy to improve patients’ outcomes. This new method provides a potentially direct avenue to treat tumors and reactivate the immune system,” said Shah.

“Our work demonstrates that tumors have lost the ability to detoxify ammonia leading to build up,” said Shah. Additionally, it’s possible that ammonia buildup is not limited to colorectal cancers. According to Shah, this finding may help to explain why some cancers are resistant to treatment.

“Only about 20-30% of all cancer patients are sensitive to immunotherapy. 70% of patients don’t derive any benefit from it,” Shah said, adding, “Now, we have a mechanism that could explain this resistance in tumors beyond colon cancer.”