Reviving tired T cells to improve immuno-oncology treatments

Human T cell
Targeting the protein TOX in exhausted T cells could improve immuno-oncology treatments, a University of Pennsylvania team suggested. (NIAID)

A population of immune cells known as effector T cells are important in the fight against cancer and infectious diseases, because they produce substances that kill the pathogenic cells. Problem is, these T cells can become exhausted.

A team at the University of Pennsylvania has discovered a protein that helps determine the fate of exhausted T cells—and that might be able to be targeted to improve immuno-oncology treatments.

The protein, called TOX, controls the evolution of exhausted T cells. Specifically, high levels of TOX sustained over a long period of time promote the cells’ survival, which may cause cancer to persist or progress, they reported in the journal Nature.

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The Penn researchers discovered that the amount of TOX in a T cell orchestrates the body’s response to infections or cancer by controlling the balance of effector T cells and exhausted T cells. Furthermore, TOX shapes the cells’ genomes, making it difficult for some genes to produce proteins. That may explain why it’s so challenging to transform exhausted T cells into effector T cells, they suggested.

RELATED: Reinvigorating CAR-T cells in solid tumors by targeting a family of proteins

Combating T cell exhaustion is of particular interest to researchers developing chimeric antigen receptor T cell (CAR-T) therapies, which involve taking T cells from patients and engineering them so they can recognize and attack their cancers. The technology has been revolutionary in the treatment of certain blood cancers, but it doesn’t work for everyone and it has been difficult to translate to solid tumors—a problem that may be related, in part, to T cell exhaustion.

Several approaches to reviving T cells have been proposed. In February, researchers at the La Jolla Institute for Immunology reported their discovery that removing three proteins called Nr4a transcription factors could reinvigorate exhausted CAR-Ts in rodent studies.

Reviving tired T cells is also of interest to researchers who are trying to improve the response rate to checkpoint-inhibiting drugs like Merck’s PD-1 blocker Keytruda. Scientists at Emory University, for example, have proposed that stimulating an immune protein called CD28 on the surface of T cells could boost responses to PD-1 inhibitors.

Combination treatments could be key in priming T cells so they won’t become exhausted before responding to checkpoint inhibition. Apexigen generated some excitement at the recent American Association for Cancer Research (AACR) meeting for its CD40-activating drug, APX005M, which performed well in pancreatic cancer patients when combined with Bristol-Myers Squibb’s PD-1 inhibitor Opdivo and chemotherapy.

The Penn researchers believe their insights into TOX and its role in shaping T cell identity could be used to develop new immunotherapies.

"The discovery of TOX as the key regulator of exhausted T cells now allows us to envision immunotherapies that target, or engineer, TOX to reverse or prevent exhaustion and improve immunity to infections or cancer," said senior author E. John Wherry, Ph.D., chair of the department of pharmacology and director of Penn's Institute of Immunology, in a statement.

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