Natural antioxidant helps improve immune-based therapies

Long-time Medical University of South Carolina collaborators Dr. Shikhar Mehrotra (left) and Dr. Xue-Zhong Yu (right) author papers showing that a natural antioxidant can modulate T cell activity in cancer immunotherapy and graft-vs.-host disease, respectively ( Emma Vought, Medical University of South Carolina).

Researchers, Shikhar Mehrotra, PhD and Xue-Zhong Yu, MD from the Medical University of South Carolina (MUSC) have discovered a way to 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.

Though they study different models, Mehrotra and Yu are long-time collaborators: “Our collaboration is a common interest in the biology of T cells and how to manipulate them to benefit different disease conditions,” Yu explained.

Mehrotra, an associate professor in the College of Medicine and co-scientific director of the Centre for Cellular Therapy at MUSC Hollings Cancer Center, recently published a study that showed thioredoxin extends the life of adoptive T cells by neutralising toxic reactive oxygen molecules (ROS).

“Treating anti-tumour T cells with recombinant thioredoxin before adoptive transfer not only imparted high anti-oxidant capacity,” explained Mehrotra. “It also metabolically programmed these cells to withstand nutrient competition with the tumour – which resulted in better tumour control.”

Mehrotra and his team used a strain of mice that overexpress thioredoxin and performed a standard ACT procedure. They observed increased T-cell viability and anti-tumour 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 tumour. The results suggest that treating human T cells with thioredoxin before administration will increase cell viability and improve the anti-tumour effect of ACT in patients.

Yu (a professor in the College of Medicine and S C SmartState Endowed Chair in Cancer Stem Cell Biology and Therapy) and his team study the development of graft-versus-host disease (GVHD) in recipients of HSCT.

Using a mouse model, Yu’s lab tested the effect of thioredoxin on donor T cells. Yu’s study also found that thioredoxin’s antioxidant effect decreased toxic ROS in donor T cells, made them less reactive to the patient’s healthy tissues and thereby prevented the development of GVHD.

“Thioredoxin is a natural product with no toxicity. We can use it to fine-tune T-cell activation in a way that will reduce graft-vs-host disease but maintain the anti-tumour effect,” Yu said.

The next step for both projects is to induce human tumours into mice and test the effect of thioredoxin-treated T cells in both ACT and HSCT models. This will determine if it can be moved to be tested on patients.

Both studies were published in the Journal of Biological Chemistry.