Mayo Clinic researchers announced on Aug. 3 the identification of a protein, TRAILshort, that cancer cells use to suppress the body's immune response. The discovery could lead to new treatments aimed at improving the effectiveness of cancer immunotherapies.
The study, published in the Journal of Clinical Investigation, found that TRAILshort acts as an 'off switch' for T cells—the primary cells responsible for attacking cancer and virus-infected cells. In preclinical models, blocking TRAILshort restored T-cell activity and improved immune responses. Researchers also observed that TRAILshort reduces the effectiveness of chimeric antigen receptor-T cell therapy (CAR-T cell therapy), a leading form of cancer immunotherapy. The findings suggest therapies targeting TRAILshort could enhance CAR-T treatment and potentially benefit other forms of immune-based therapies.
Mayo Clinic researchers first discovered TRAILshort during HIV studies nearly 15 years ago. In 2020, they found that certain cancers also produce this protein but did not know how it suppressed T-cell activity until now. Elevated levels of TRAILshort were identified in melanoma, lung, breast, pancreatic and ovarian cancers as well as Hodgkin lymphoma. Increased levels were also seen in infectious diseases such as COVID-19, tuberculosis and hepatitis C.
Using specific antibodies and engineered preclinical models, researchers determined that TRAILshort activates SHP-1—a molecular brake—shutting down T cells before they can attack diseased cells. "This is the first study to show that TRAILshort doesn't just block cell death—it also acts as a signaling molecule that directly suppresses T-cell activity," says Shahrzad Jalali, Ph.D., research scientist at Mayo Clinic and lead author of the study.
Saad Kenderian, M.B.Ch.B., oncologist at Mayo Clinic Comprehensive Cancer Center and co-author, said, "Discovering the role of TRAILshort and how it inhibits CAR-T cells opens the door for a new therapeutic strategy to improve their activity." Beyond oncology applications, researchers say targeting or supplementing TRAILshort may eventually help regulate harmful immune activity in autoimmune diseases or transplantation without broadly suppressing immunity.
Dr. Badley said, "In cancer, there's too much TRAILshort so our goal is to get rid of it with antibodies that remove it. In autoimmune disease there's not enough TRAILshort so our goal is to deliver more." He added, "What excites us most is that this discovery gives us a new actionable way to regulate the immune system... By targeting TRAILshort we may be able to strengthen immune responses against cancer and chronic infections or... reduce harmful immune activity." Additional studies are needed to determine whether these approaches are safe and effective.
