Even when immunotherapy “takes the brakes off” a cancer patient’s immune cells, these cells may remain stuck in neutral, or they may act as though they are out of gas, exhausted. Immunotherapy, then, may need to rejuvenate immune cells, specifically T cells, in addition to taking the brakes off via checkpoint blockade. That’s the idea behind recent work accomplished by scientists based at St. Jude Children’s Research Hospital.
Working with preclinical models, these scientists have discovered how 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 nonresponsive or experience a relapse of their disease. Such immunotherapy failures, it has been suggested, may be due to T-cell exhaustion.
The St. Jude scientists, led by Ben Youngblood, Ph.D., 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. Moreover, the scientists determined that a chemotherapy drug already in use can reverse epigenetically mediated exhaustion.
Details appeared June 22 in the journal Cell, in an article entitled “De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation.” According to this article, blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection.
“Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 [programmed cell death protein 1] blockade treatment,” wrote the article’s authors. “Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB [immune-checkpoint blockade].”
These findings offer 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.
“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,” said Dr. Youngblood. “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.”
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,” recalled Dr. Youngblood.
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.
“Now that we have shown this is an intrinsic property of T cells, it means you can pull out the T cells, treat them, and reintroduce them to attack the cancer,” asserted Dr. Youngblood. “With such approaches, you limit toxicity to the patient.”
The researchers found that treating the T cells with a widely used immune-checkpoint inhibitor called PD-1 did not erase the epigenetic exhaustion finding. “This finding shows that, at least for this particular therapy, the therapeutic effect may be inherently transient and prone to relapse,” noted Dr. Youngblood.
However, when researchers treated mice that had tumors with the chemotherapy drug decitabine, their T cells showed properties indicating enhancement. Decitabine acts to thwart the epigenetic DNA methylation off-switch.
“We found this treatment reversed the exhausted state,” said Dr. Youngblood. “When we treated the mice with PD-1, their T cells proliferated actively and had the properties of rejuvenated T cells.” The researchers found the enhanced T-cell proliferation was coupled with significant control of tumor growth. The findings suggest that combining epigenetic reprogramming with immune-checkpoint blockade could enhance treatment efficacy.
Dr. Youngblood said the findings have important implications for treating chronic viral infections, notably HIV.
“We know the T cells in patients with HIV become exhausted,” he pointed out. “Although there are very effective drugs that reduce the viral load to undetectable levels, that therapy is costly and is not a cure. I'm optimistic that the immune system holds the ultimate promise of a cure for HIV infection, and basic findings such as ours represent one step toward that cure.”
Dr. Youngblood emphasized the findings reported in Cell were made using viral and tumor models in mice, not humans. So, he and his St. Jude colleagues are now exploring the epigenetic exhaustion programs in human cancers to determine whether they are similar to the one they identified in mice.
The researchers are also seeking to understand differences and similarities between the T-cell exhaustion programs in cancers and viral infections. Such basic understanding will aid the application of immunotherapy to chronic viral infections such as HIV, Dr. Youngblood said.