Immune hematology

The researches find that the improve immune-based treatments, such as adoptive T-cell therapy (ACT) and hematopoietic stem cell transplantation (HSCT); by modulating T-cells with thioredoxin, a powerful, naturally occurring antioxidant molecule. ACT is a cancer immunotherapy in which the patient’s own immune cells (T-cells) are engineer to recognize cancer cell-specific markers. First, the patient’s blood is collect; then T-cells are remove and genetically modify to attack cancer cells. Finally, the modified T-cells are re-administer to the patient.

Immune-based treatments

ACT is currently used for patients with leukemia and lymphoma. However, a major downside to the treatment is that the re-administered T cells do not live long, leading to relapse. HSCT is a classic immune-base treatment that requires a donor to supply stem cells; which are then administered to the patient to help them produce more immune cells to fight blood-related diseases, including blood cancers.

A severe side effect of HSCT is graft-versus-host disease (GVHD); which occurs when the donor T-cells attack the recipient’s healthy tissues instead of diseased cells. Though they study different models; Mehrotra and Yu are long-time collaborators. Both are dedicated to understanding T-cell function. “Our collaboration is a common interest in the biology of T-cells and how to manipulate them to benefit different disease conditions,” Yu explains.

Donor T-cells attack

Mehrotra is an associate professor in the College of Medicine and co-scientific director of the Center for Cellular Therapy at MUSC Hollings Cancer Center. He and his team recently published a study in the Journal of Biological Chemistry that showed that thioredoxin extends the life of adoptive T-cells by neutralizing toxic reactive oxygen molecules (ROS).

Tumor environments have high concentrations of ROS. Without antioxidants such as thioredoxin; ROS will damage the cell and eventually cause cell death. “Treating anti-tumor T cells with recombinant thioredoxin before adoptive transfer not only imparted high anti-oxidant capacity;” explained Mehrotra.

Treating anti-tumor

“It also metabolically programmed these cells to withstand nutrient competition with the tumor which resulted in better tumor control.” The team at MUSC used a strain of mice that overexpress thioredoxin and performed a standard ACT procedure. They observed increased T-cell viability and antitumor activity from mice overexpressing thioredoxin.

They confirmed the findings by engineering human T-cells to overexpress thioredoxin and again observed prolonged T-cell lifespan at the site of the tumor. The results suggest that treating human T-cells with thioredoxin before administration will increase cell viability and improve the anti-tumor effect of ACT in patients. Yu is a professor in the College of Medicine and S.C. SmartState Endowed Chair in Cancer Stem Cell Biology and Therapy. Yu and his team at MUSC study the development of graft-versus-host disease (GVHD) in recipients of HSCT.