A fiery form of cell death helps trigger regeneration of a critical immune organ after damage, according to preliminary work in mice, presented Dec. 7 by Fred Hutchinson Cancer Research Center scientists at the 2020 virtual annual meeting of the American Society of Hematology.
The findings could help researchers develop therapies to enhance repair of the thymus after damage from cancer treatment, infection or aging. By boosting immune function, such therapies may also someday improve the effectiveness of vaccines or certain cancer immunotherapies.
The scientists discovered that radiation damage to the immune organ, known as the thymus, caused a change in the way that certain immune cells die. These cells switch to an inflammatory type of cell death, pyroptosis, and release molecules that flip a master regenerative switch.
“What we think is going on is that acute pyroptosis releases damage-associated molecules to stimulate the regeneration response,” said Hutch regenerative medicine researcher Dr. Jarrod Dudakov, the study’s senior author.
Dudakov Lab staff scientist Dr. Sinéad Kinsella and research technician Cindy Evandy found one molecule that works directly on the cells within the thymus that stimulate regeneration. They showed that a research compound that mimics the molecule’s action also enhanced thymic repair after radiation-induced damage. Dudakov and his team are currently working to translate these findings into a treatment for patients.
The thymus is a small immune organ snuggled around the windpipe, just above the lungs. It’s where crucial immune cells, known as T cells, grow and develop. T cells help the body fend off threats from outside and inside the body, including viruses and cancer cells. To do so, they employ a specialized molecular targeting system, called the T-cell receptor, or TCR. Each new T cell has a unique TCR that allows it to target a unique threat. A properly working thymus produces a hugely diverse range of T cells, known as the T-cell repertoire.
“The thymus is essential for producing a wide diversity of the TCR repertoire,” said Kinsella, who spearheaded the work and presented the findings at ASH. “And this wide diversity is critical for recognition of a wide variety of unknown pathogens. Without diversity, unknown pathogens aren’t recognized as effectively and cancer immunosurveillance is less successful.”
When a person’s thymus makes fewer T cells, their TCR repertoire also becomes less diverse. This makes it more likely that a microbe or cancer cell can slip through a “hole” in the T-cell defenses, unrecognized.
T cell production by the thymus naturally wanes with age, but stress, toxic chemotherapy, radiation or infection can also torpedo thymic output.
“But the thymus actually has this remarkable capacity to regenerate itself,” Dudakov said. “We’re really interested in that phenomenon. What are the mechanisms that drive that natural regeneration?”
Ultimately, Dudakov aims to develop therapies that help patients by harnessing the thymus’ natural capacity to repair itself.
There are many situations where increasing thymic output could help patients, Dudakov and Kinsella said.
“We're hoping that by boosting thymic function, we can improve clinical outcomes following [bone marrow] transplants. We're also hoping we can improve clinical outcomes in other cancer patients,” Dudakov said.
Bone marrow transplant patients receive donated bone marrow cells to replace their own cancerous blood cells. But first their cancer must be wiped out with toxic chemotherapies — drugs that also kill off many healthy, noncancerous immune cells, including T cells developing in the thymus. It can take years for T-cell numbers to reach pre-transplant levels, but therapies that speed thymic repair could reduce the time that patients are immunosuppressed and vulnerable to infection.
Dudakov also expects such therapies to improve the effectiveness of certain cancer immunotherapies. Checkpoint inhibitors like pembrolizumab (Keytruda) and ipilimumab (Yervoy) release molecular brakes that rein in a patient’s own cancer-fighting T cells — but they only work if those T cells already exist within the patient. A therapy that increases T cell numbers and broadens the TCR repertoire could ensure that these patients have the T cells they need to fight their tumor.
The thymus is a complex organ. It contains many T cells at different stages of development, plus other cell types that help put the fledgling T cells through their paces. Not all T cells in the thymus make it out; they first must run a gauntlet. T cells whose TCRs barely work don’t make the cut, nor do T cells whose TCRs work a little too well and may risk triggering attacks against self — autoimmunity.
“There’s this Goldilocks zone in the middle — the just-rights — that get through,” Dudakov said.
The just-right cadre of T cells make up only about 1% of developing T cells. The 99% that fail, die.
Working in mice, Dudakov and Kinsella had previously shown that this death, which occurs as a type of programmed cell death known as apoptosis, acts as a brake on thymic regeneration. When the thymus is damaged by (for example) toxic cancer treatment, T cells stop dying by apoptosis; this releases the brake and allows the thymus to regenerate.
Dudakov also previously identified two molecules that promote thymic regeneration, known as BMP-4 and IL-23, released by accessory cells within the organ.
“We've got these distinct pathways, and they seem to be triggered by the damage itself,” Dudakov said. “But what is the common triggering mechanism? What is it about the damage that initiates this particular response? And this is something that really hasn't been addressed in any tissue.”
Kinsella found that thymic regeneration has a gas pedal in addition to a brake. In mice, she used total body irradiation, or TBI (which is used to treat some blood cancers and tanks production of T cells), to study post-damage thymic regeneration. She found that after TBI, T cells died in a new way, switching from apoptosis to pyroptosis, a form of cell death that triggers inflammation.
“Apoptotic cells degenerate and shrink. Pyroptotic cells basically burst,” Kinsella said.
Many molecules spewed by pyroptotic cells act as damage signals to other nearby cells. One such molecule is ATP, a molecular form of energy that powers many cellular processes. Kinsella found that ATP activates surrounding cells to promote thymic regeneration. It appears to be the master signal that can activate the same response triggered by BMP-4 and IL-23.
When Kinsella and teammates dosed mice with ATP after TBI, their thymuses regenerated better than those of mice who’d undergone TBI without receiving ATP.
“But how do you translate that into a therapeutic, when you can’t administer ATP clinically?” she said.
Instead, Kinsella was able to pinpoint the receptors through which the thymus’s regeneration-promoting cells respond to ATP. The team identified a research compound that works through these receptors and found that it had a similar regeneration-boosting effect on the thymuses of irradiated mice as ATP.
As a step toward moving the findings to the clinic, Kinsella and Dudakov have filed patent applications for systems and methods to boost thymic function by targeting this pathway.
And Dudakov is not done revealing the mysteries of the regenerating thymus.
His team is also testing whether the research compound may be able to counteract age-related thymic decline, which causes older people to be more vulnerable to infection and less responsive to vaccines. And he is working to test whether measures of thymic function could be used to predict how cancer patients are likely to respond to checkpoint inhibitors.
“This is part of our challenge, to make people aware that the thymus matters,” he said.
This work was funded by the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute on Aging, a Scholar Award
from the American Society of Hematology, a John Hansen Research Grant from DKMS and a New Investigator Award from the American Society for Transplantation and Cellular Immunotherapy.
Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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