Cancer Cells Use a “Molecular Brake” to Block T-Cell Attacks; Blocking It May Overcome CAR-T Resistance

A protein that cancer cells use to block T-cell attacks has been identified for the first time. The findings suggest that blocking this protein could reverse resistance to CAR-T therapy, considered one of the most advanced cancer immunotherapies currently available.

Researchers at the Mayo Clinic said in a paper published on the 26th in the Journal of Clinical Investigation (JCI) that a protein called TRAILshort acts as a “molecular brake” that switches off immune cells’ attacks.

The researchers identified for the first time that TRAILshort suppresses T-cell function by activating a protein called SHP-1 before T cells recognize and attack cancer cells. In preclinical models, blocking TRAILshort restored T-cell activity and improved the immune response.

TRAILshort levels were elevated in melanoma, lung cancer, breast cancer, pancreatic cancer, ovarian cancer and Hodgkin lymphoma. Levels also rose in infectious diseases such as COVID-19, tuberculosis and hepatitis C.

The researchers also found that TRAILshort substantially reduces CAR-T therapy’s ability to control tumors. Blocking it restored immune activity, and the researchers said a therapy targeting TRAILshort could be a new strategy for improving CAR-T treatment outcomes.

Andrew Badley, MD, the paper’s corresponding author, said, “TRAILshort appeared in almost every situation in which the immune system breaks down or malfunctions, including cancer, HIV, COVID-19, tuberculosis, lupus and Crohn’s disease.” He added, “This may not be a phenomenon limited to a specific disease; we may have found a fundamental switch in human immunity.”

The researchers said TRAILshort could also serve as a biomarker for identifying tumors that are more likely to respond to targeted therapy.

The protein may also have applications beyond cancer, including in autoimmune diseases and organ transplantation. “In cancer, TRAILshort is present in excessive amounts, so the goal is to remove it with an antibody; in autoimmune diseases, it is deficient, so the goal is to provide more,” Badley said.

The researchers added, however, that further studies are needed to assess safety and efficacy in patients.