University of Pennsylvania researchers identify the protein TOX as crucial to the body’s response to T-cell exhaustion.

The immune cells known as effector T-cells fight both infectious agents and tumors by producing substances that kill harmful cells. Effector cells get tired, however, and become exhausted T-cells. Medical researchers have long desired to develop a way to prevent T-cells from becoming exhausted or converting those that do back into effector T-cells, particularly for developing chimeric antigen receptor T-cell (CAR-T) therapies and checkpoint-inhibitors.

Work from the University of Pennsylvania may make reaching that goal more likely. Researchers at the school have identified the TOX protein as playing a key role in determining the fate of exhausted T-cells.

The evolution of exhausted T-cells is controlled by the level of TOX. Sustained high levels of the protein promote the survival of exhausted T-cells at the expense of effector cells, which may allow tumors to remain or even grow. In addition, the genomes of T-cells are affected by TOX. In some cases, the genes are not able to produce proteins, which may be why it is difficult to convert exhausted T-cells into effector T-cells. The researchers believe these insights could be useful in developing new immunotherapies that target or engineer TOC to reverse or prevent exhaustion.