Antioxidant thioredoxin may soon be used to improve cancer treatment

Researchers at the Medical University of South Carolina (MUSC) have discovered the use of thioredoxin – a natural antioxidant intended to modulate T cells of the immune system. This could be a major step towards improving the current immunotherapies, such as adoptive T-cell therapy (ACT) and hematopoietic stem cell transplantation (HSCT).

The studies were funded by the National Institutes of Health headed by Shikhar Mehrotra and Xue-Zhong Yu, respectively. They were published in the Journal of biological chemistry and Journal of Clinical Investigation respectively. The first study conducted by Mehrotra was published in November 2018 and entitled "Thioredoxin-1 improves the immuno-metabolic phenotype of anti-tumor T cells".

The second was published in May this year and titled "Thioredoxin-1 limits T cell response and T-cell pathogenicity in graft-versus-host disease". Mehrotra is an Associate Professor at the College of Medicine and Co-Scientific Director of the Center for Cellular. MUSC therapy Hollings Cancer Center and Yu is a professor at the Faculty of Medicine and the SC Smart State Chair in Biology and Cancer Stem Cell Therapy.

Dr. Shikhar Mehrotra (left) and Dr. Xue-Zhong Yu (right), two long-time collaborators at the South Carolina Medical University, have shown that a natural antioxidant can modulate the body's health. T cell activity in cancer immunotherapy and graft-versus-host disease, respectively. Image credit: Emma Vought, Medical University of South Carolina

The team of researchers explains that ACT is a form of immune therapy used in cancers where the patient's own T cells are modified so that they can identify certain markers of cancer and target cancer cells to kill them. selective while preserving healthy cells. For this, the patient's T cells are removed from the body and designed to recognize specific cancer markers before they are reinjected into the patient. ACT has shown promising results in leukemias and lymphomas. However, these re-injected T cells have a short life span and often die, leading to the return of cancer.

Another common form of immune therapy is HSCT, in which a donor is used for the stem cells which are then injected into the patient. These stem cells multiply to form immune cells that could fight cancer. HSCT is often complicated by graft-versus-host disease (GVHD), in which the donor's cells do not recognize the patient's cells and do not attack the healthy cells of the host instead cancer cells. .

Yu explained that this new study from their labs showed that thioredoxin, an antioxidant, is able to prolong the life of adoptive T cells by neutralizing molecules of reactive oxygen species (ROS) toxic. This solves the major problem of ACT, where the short life span of Te cells was the main problem leading to relapse, the researchers explained. Yu said, "Our collaboration is of common interest for T cell biology and how to manipulate them to improve different disease conditions."

They add that cancers and tumors often have very high levels of ROS that result in cell damage and death. Mehrotra explained: "Treating antitumor T cells with recombinant thioredoxin prior to adoptive transfer not only conferred high antioxidant capacity." The team explained that the expression of thioredoxin in humans and in the mouse was 90% identical and that the mouse models were therefore adapted to this experiment.

For the study, the team led by Mehrotra used a special mouse strain that could produce more thioredoxin and used ACT on them. They noted that in these mice, T cell lifespan was longer and that antitumor activity was therefore also greater. Then, the team has now modified and developed the adoptive T cells so that they can overexpress thioredoxin. It was also found that these T cells existed longer and that their antitumor effects were also improved.

Yu's team worked on the expression of thioredoxin on donor T cells to be used in HSCT. The team used mouse models to see that there was a prolongation of life span among donor T cells. When the expression of thioredoxin increased in these donor T cells, their ROS decreased. This meant that these donor cells were less likely to attack the patient's healthy cells and thus prevented the onset of GVHD. Yu explained, "Thioredoxin is a natural product with no toxicity. We can use it to refine the activation of T lymphocytes so as to reduce graft-versus-host disease while maintaining the anti-tumor effect. They also noted a reduction in CD98 expression on T cells with more thioredoxin. . CD98 is an amino acid transporter that we see on activated T cells, the team wrote. When CD98 levels decrease, T cells absorb less glutamine. It also reduces the risk of GVHD, writes Yu's team.

Yu and Mehrotra are now united to collaborate on their project and test T cells with increased expression of thioredoxin on human tumors developed in laboratory mice. If this step succeeds with ACT and HSCT working safely and effectively, clinical trials on humans could be planned next, they added.