Blocking TRAILshort in preclinical models reactivates T cells and boosts immune responses, while reducing the effectiveness of CAR-T therapy when present, indicating that TRAILshort targeting could enhance CAR-T and other immunotherapies.

TRAILshort may serve as a biomarker to identify tumors more likely to respond to targeted therapies, guiding personalized treatment strategies.

Lead author Shahrzad Jalali, Ph.D., and senior author Andrew Badley, M.D., spearhead a broader Mayo Clinic collaboration on this work.

Elevated TRAILshort levels have been observed across multiple cancers (including melanoma, lung, breast, pancreatic, ovarian, and Hodgkin lymphoma) and infectious diseases, suggesting a broad role in immune regulation.

Mayo Clinic researchers identify TRAILshort as an immune off switch that helps cancer cells suppress T-cell activity and evade destruction, by activating SHP-1.

TRAILshort activates SHP-1, dampening early TCR signaling and diminishing T-cell activation.

Removing or inhibiting TRAILshort restores T-cell signaling and improves immune responses against cancer and chronic infections, highlighting TRAILshort as a potential therapeutic target in cancer immunotherapy.

The findings were published in the Journal of Clinical Investigation, with full author, disclosure, and funding details available in the article.

Beyond inhibiting cell death, TRAILshort is described as a signaling molecule that suppresses immunity, expanding its functional role.

The work is part of Mayo Clinic’s Precure Research initiative, which aims to detect disease-related changes early and guide therapeutic development.

Precure Research at Mayo Clinic focuses on early detection of disease-related changes to improve treatment outcomes.

Therapeutic implications include developing antibodies to remove TRAILshort and, conversely, possibly delivering TRAILshort to dampen harmful immune activity in autoimmune or transplant settings, though all approaches are experimental.