Natural antioxidant helps improve immune-based therapies by modulating T-cells

July 10, 2019
Long-time collaborators Dr. Mehrotra (left) and Dr. Yu (right) author papers showing that a natural antioxidant can modulate T cell activity in cancer immunotherapy and graft-vs.-host disease, respectively. Photo by Emma Vought

Shikhar Mehrotra, Ph.D. and Xue-Zhong Yu, M.D., National Institutes of Health-funded researchers at the Hollings Cancer Center at 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.

ACT is a cancer immunotherapy in which the patient's own immune cells (T-cells) are engineered to recognize cancer cell-specific markers. First, the patient's blood is collected, then T-cells are removed and genetically modified to attack cancer cells. Finally, the modified T-cells are readministered to the patient.

ACT is currently used for patients with leukemia and lymphoma. However, a major downside to the treatment is that the readministered T-cells do not live long, leading to relapse.

HSCT is a classic immune-based 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 longtime 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.

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 antioxidant capacity," says Mehrotra, "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 anti-tumor 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 administering them will increase cell viability and improve the anti-tumor effect of ACT in patients.

Yu is a professor in the College of Medicine and the S.C. SmartState Endowed Chair in Cancer Stem Cell Biology and Therapy. Yu and his team at MUSC study the development of GVHD in recipients of HSCT.

Using a mouse model, Yu's lab tested the effect of thioredoxin on donor T-cells. Like Mehrotra's study with adoptive T-cells, Yu's study found that thioredoxin's antioxidant effect decreased toxic ROS in donor T-cells, making them less reactive to the patient's healthy tissues and thereby preventing the development of GVHD. These results were published in the Journal of Clinical Investigation.

"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-versus-host disease but maintain the anti-tumor effect," Yu says on the new finding.

Mehrotra and Yu plan to continue to work closely to develop this new advancement in T-cell immune therapy.

The next step for both projects is to induce human tumors 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 the clinical setting to be tested on patients.

Hollings Horizons Magazine

This story appears in the fall 2019 issue of Hollings Horizons, a publication of MUSC Hollings Cancer Center designed to show readers how we are committed to being at the forefront of cancer research.

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