Shikhar Mehrotra, Ph.D. and Xue-Zhong Yu, M.D., National Institutes of Health-funded researchers 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 re-administered to the patient.
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-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 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.
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.
"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.
Using a mouse model, Yu's lab tested the effect of thioredoxin on donor T-cells, and the results were published in the Journal of Clinical Investigation. Like Mehrotra's study with adoptive T-cells, Yu's study 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 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 anti-tumor effect," Yu reports 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 clinic to be tested on patients.
The content of the articles summarized here is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, which funded the studies. Both studies received support from the South Carolina Clinical & Translational Research Institute, an NCATS CTSA hub. Mehrotra received pilot project funding and several members in Yu's laboratory received TL1 funding.
Founded in 1824 in Charleston, MUSC is the oldest medical school in the South, as well as the state's only integrated, academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and 700 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state's leader in obtaining biomedical research funds, in fiscal year 2018, MUSC set a new high, bringing in more than $276.5 million. For information on academic programs, visit http://musc.
As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available, while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians' practice plan, and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2018, for the fourth consecutive year, U.S. News & World Report named MUSC Health the number one hospital in South Carolina. To learn more about clinical patient services, visit http://muschealth.
About Hollings Cancer Center
The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 100 faculty cancer scientists and 20 academic departments. It has an annual research funding portfolio of more than $40 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.
About the South Carolina Clinical and Translational Research Institute
The South Carolina Clinical and Translational Research (SCTR) Institute, a National Institutes of Health Clinical and Translational Science Awards hub, is the catalyst for changing the culture of biomedical research, facilitating sharing of resources and expertise, and streamlining research-related processes to bring about large-scale, change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice. For more information, visit https:/