New study identifies molecular players in ‘dead man’s switch’ that triggers key immune organ’s regeneration after damage.
The pandemic has put immune function — and how to boost it — at top of mind. Most recommendations for boosting immune responses focus on lifestyle choices, including adequate sleep, a solid exercise program and a well-rounded diet, that can keep our immune health in tip-top shape. But new work from scientists at Fred Hutchinson Cancer Research Center raises the possibility that immune-regenerating drugs could someday be in our toolbox.
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“The goal is to develop therapies that leverage our natural regenerative processes,” said Dr. Jarrod Dudakov, the Hutch regenerative immunologist who led the project, published today in the scientific journal Cell Reports. The work outlines a molecular ‘dead man’s switch’ that triggers regeneration of the thymus after damage, and shows that an experimental compound that mimics this switch can boost immune function.
Dudakov and staff scientist Dr. Sinéad Kinsella outlined the molecular players that link damage to the thymus, a small but critical immune organ located just in front of the heart, to its regeneration. In mice, they were able to trigger thymic renewal and boost immune function by using an experimental compound that targets a central molecule in the pathway.
Strategies that improve immune function could help stave off infection in anyone with lowered immune function, which includes people undergoing treatment for cancer or anyone experiencing aging, Dudakov noted. He also envisions future treatments that leverage the thymus’ natural regenerative processes to boost immune-based therapies, from vaccines to engineered anti-cancer immune cells.
Taking advantage of natural regeneration
Dudakov and Kinsella’s studies focus on the thymus, an organ in which immune cells known as T cells develop. T cells can help the body fight off infection and cancer by using specialized T-cell receptors, or TCRs, to hunt down infected or diseased cells. Our bodies can’t know which infections we’ll encounter in the future, or where tumors will later arise, so we churn out millions of T cells with unique TCRs to deal with as-yet unmet dangers.
There are a lot of medical situations in which Dudakov envisions that boosting our T cell numbers could be helpful. Certain cancer treatments, such as chemotherapy, radiation and bone marrow transplant, wipe out immune cells, including T cells, and leave patients vulnerable to infection as they wait for their immune systems to bounce back. T cell-boosting treatments could also make vaccines more effective and improve cancer immunotherapies.
“But in each of those situations, you depend on a T cell existing that can see the infected or cancer cell,” Dudakov said.
This means that damage to the thymus that also wipes out T-cell production could effectively leave our immune systems blind (or at least very nearsighted) to disease.
Unfortunately, the thymus is a delicate organ. Chemotherapy, radiation, even infection and aging all do a number on its ability to shepherd developing T cells out into the body. (And aging-related thymic decline isn’t gradual: Puberty pushes the thymus into a permanent downhill skid.)
“But fortunately, the thymus has an amazing capacity for renewal,” Dudakov said.
He wants to develop therapies that take advantage of this natural regenerative capacity to help boost people’s ability to fight cancer and fight infection.
Orchestrating thymic renewal
Prior to the current study, Dudakov and Kinsella had sketched the rough outlines of the thymus’ renewal processes. This included identifying molecules that orchestrated two separate regenerative pathways (one triggered by a molecule called IL-22, and another by Bmp-4), and showing that it is the damage itself that triggers the thymus to renew. They’d also discovered that damage to the thymus sparks its regeneration by temporarily destroying a normal thymic developmental process.
T cells developing in the thymus undergo a rigorous “education” process that ensures that we aren’t stuck with a lot of mature T cells that either can’t recognize any signs of disease, or are primed to attack our healthy tissue instead of infected cells. Most T cells don’t make the cut and get weeded out, dying by the thousands.
Prior work by Dudakov and Kinsella suggested that dead and dying T cells acted as a brake on regeneration. When damage to the thymus wipes out T cells — surviving and dying alike — this brake is removed, and renewal mechanisms roar in to fill the void.
Though Kinsella and Dudakov knew that dying T cells somehow acted as a brake to keep IL-22 and Bmp-4 — and thymic regeneration — suppressed, they didn’t know how. Outlining the molecules that made up this sensor and suppressor system (the dead man’s switch that activates after damage obliterates the T cells) would reveal potential targets they could manipulate to promote regeneration.
The cells that help the thymus refill itself with T cells aren’t T cells themselves, but accessory cells that support young T cells as they clear — or miss — their developmental hurdles. Kinsella found that it’s these accessory cells that sense dying T cells. With Dudakov Lab technician Cindy Evandy, she then outlined the molecular relays that lead from thymic damage to Bmp-4 and IL-22 (which activate thymus regeneration), identifying several key molecules along the way. Then, the researchers tested whether they could intervene.
Kinsella and Evandy assessed whether blocking one of the players, called Rac1, (thereby boosting IL-22 and Bmp-4) helps improve thymic function after damage. They treated mice with an experimental Rac1 inhibitor after exposing them to radiation (similar to the thymus-blasting regimen that patients receive before bone marrow transplant). Mice treated with the Rac1 inhibitor produced more T cells than either untreated mice or treated mice that lacked a molecule in the T cell-death sensing pathway.
The findings open a new window on regeneration in the thymus, Kinsella said: “Before this study, not a lot was known about negative regulators of regeneration.”
Next step: drug development
The researchers now are working to translate their findings to the clinic — though they caution that there’s quite a way to go. She and Dudakov are also working to demonstrate that boosting thymic regeneration can also boost immune responses in older mice, a step toward developing immune-boosting treatments to help counteract age-related immune decline in humans. Ideally, such treatments would help make vaccines — perhaps even including those helping to curb the COVID-19 pandemic — more protective and long-lasting to reduce the need for boosters.
The researchers are also digging deeper into the connection between cell death and renewal that they discovered in the thymus and think may extend to other tissues.
Perhaps the biggest hurdle right now is the lack of a Rac1 inhibitor available for clinical use. But Dudakov and Kinsella are hopeful; molecules related to Rac1, collectively called Rho GTPases, have been implicated in many diseases, and are an active area of investigation by pharmaceutical companies.
“To move it forward, it’s really going to require a drug itself,” Dudakov said. “And that’s where we’re at, at the moment, trying to develop compounds that could be used clinically.”
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Research Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University.