St. Jude Children’s Research Hospital discovery of the mechanism of T cell exhaustion will lead to treatments to enhance immunotherapies against cancers and such viruses as HIV.
St. Jude Children’s Research Hospital immunologists have discovered how immune cells called T cells become “exhausted” – unable to do their jobs of attacking invaders such as cancer cells or viruses. The finding is important because patients treated with immunotherapies against cancers are often non–responsive or experience a relapse of their disease, and it has been suggested that these challenges may be due to T cell exhaustion. In preclinical model systems studying viral infections or tumors, the researchers found that a chemotherapy drug already in use can reverse that exhaustion.

The finding offers a new pathway to more powerful and durable immunotherapies, as well as immune therapies for viruses such as HIV that would marshal the immune system to kill the virus, researchers said.

In a paper appeared in the June 29 edition of the journal Cell, researchers led by Ben Youngblood, PhD, an assistant member of the St. Jude Department of Immunology, reported findings that explain the failure of a form of immunotherapy called immune checkpoint blockade. In this treatment, patients receive a drug that releases the brakes on their T cells allowing them to kill virally infected or tumor cells. The tumor–fighting T cells detect a protein called an antigen on the cancer cells’ surface that triggers the attack. Youngblood said T cell exhaustion in such immunotherapies is a major roadblock to successful treatment.

“The clinical significance of T cell exhaustion is huge, because when a person comes into the clinic with a tumor, it is likely they have had it for many months,” he said. “And their T cells, which would be responding to that tumor, have been exposed to the tumor antigen for a long time. This may likely be why immunotherapy fails in many patients, because their T cells are already exhausted or stably repressed.”

In preclinical studies, the researchers explored the mechanism by which both viral infection and a tumor caused T cell exhaustion. They found the culprit was a so–called “epigenetic program” that repressed the T cells’ ability to respond to tumor antigens.

Epigenetic controls are molecular switches that turn genes on or off to control the cell’s machinery. While the genome of thousands of individual genes is like data stored on a computer disk, the epigenome is like a set of computer programs that control how stored data are read.

In their experiments, the researchers found that the exhaustion program was passed on to successive generations of T cells. Specifically, they found that the epigenetic program involved a process called DNA methylation, which is a key epigenetic off–switch. They also found that the exhaustion program persisted, even after the T cells were not exposed to the triggering antigen.

“We thought there should be epigenetic changes that affected the biology of the T cells, but it was a real surprise how much impact the changes had on their biology,” Youngblood said.

He and his colleagues discovered the exhaustion process was intrinsic to the T cells. This finding has important implications for immunotherapies in which a patient’s T cells are engineered outside the body to supercharge them to fight a cancer and then are reintroduced into the body.