By Christina Hernandez Sherwood
Sometimes dubbed “the soldiers of immunity,” T cells are among the most ruthless warriors in the immune system’s arsenal. These powerhouse fighters have the unique ability to periscope into individual cells to see what’s lurking inside. If the T cells spot a pathogen, they attack, destroying not only the foreign invader but the entire cell containing it. Of course, this “shock and awe” approach to viral warfare has its limits: T cells waging long-term battles eventually succumb to exhaustion, losing their full power to fight back.
Yet in recent years, researchers at Penn Medicine and beyond have made huge inroads in manipulating the complex process of T cell exhaustion to revive these immune system soldiers and, in some cases, even cure disease.
E. John Wherry, PhD, chair of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine and director of Penn’s Institute for Immunology and Immune Health (I3H), leads a lab that has studied the molecular wiring of exhausted T cells for nearly a quarter century. Wherry shares the latest on T cell exhaustion, including the newest insights from Penn researchers on how the process impacts clinical disease and therapeutics.
What causes T cells to become exhausted?
E. John Wherry, PhD
With a typical infection, T cells get control of the virus and eliminate it completely. In the process, the T cells cause a good bit of damage, which is what makes you feel sick.
T cell exhaustion happens during a prolonged response to a virus or other infection that is challenging to get rid of entirely. It arises during chronic stimulation of the immune system when the body recognizes that it might be better to live with the virus than kill yourself trying to get rid of it. We first recognized this problem in chronic viral infections, such as HIV and hepatitis. You can have T cell exhaustion in chronic non-viral infections, such as malaria. In more recent years T cell exhaustion has been appreciated to be a major problem in human cancers where that chronic stimulation of the immune system can also occur.
In T cell exhaustion, the immune system switches from destroying everything to eliminate the pathogen to learning how to manage it. T cells sit in this under-responsive state. They’re not inert. They’re partially responsive. It’s as though the body’s defense goal has changed to keep the virus in check without causing too much damage along the way.
So exhausted T cells haven’t just given up, but they change tactics to defend the body in a different way. What happens biologically in T cell exhaustion?
It is a very active process over several weeks of chronic stimulation. The T cells turn on brakes, or checkpoints. They’re being actively restrained. After weeks of chronic stimulation, they go down a separate path of differentiation. They rewire their epigenetics, or gene expression program—the way they interpret and respond to their environment—in ways that become progressively more irreversible.
Can medical treatments revive exhausted T cells?
If those brakes or checkpoints are taken away, the T cells can experience a burst of activity again. We can restore some function, essentially reinvigorating exhausted T cells to at least temporarily perform their immune functions more efficiently. If you intervene early in the process, you can perhaps have a more durable benefit to the cell.
It’s like an exhausted marathon runner. If you give them a drink with caffeine, you might get a bit more energy out of them. The result depends where you are in the race. If you do that at mile three, you’re likely to get a longer-lasting response. If you do it at mile 23, you’ll get less benefit.
How does T cell exhaustion work in patients with cancer?
T cell exhaustion has been a major barrier for cancer treatments. Nobel Prize–winning work from James Allison and Tasuku Honjo to partially reinvigorate these exhausted T cells was the breakthrough in human therapeutics. We’re now seeing drugs like YERVOY, KEYTRUDA, and OPDIVO that are curing cancer patients.
If you were diagnosed with stage IV melanoma 15 years ago, you had six months to live. We’re now completely curing about a third of those patients. Many of the rest have very substantial increases in survival. We’re seeing hundreds of thousands of people being treated with drugs targeting exhausted T cells.
How can interfering with T cell exhaustion help patients with other diseases?
We also see T cell exhaustion in autoimmunity, when immune cells are also inappropriately chronically stimulated, in this case because they recognize parts of our own body. The relationship is the opposite of cancer. When T cell exhaustion is more severe, the symptoms of autoimmunity tend to go down. This provides new ways to think about therapies for autoimmunity. You could make exhaustion more severe to cause less damage to the tissue, or even undermine the unique ability of exhausted T cells to withstand chronic stress and eliminate them completely, thereby curing autoimmunity.
How are your lab and others at Penn advancing our understanding of T cell exhaustion and ways to manipulate the process to treat diseases?
We’re excited about opportunities to reprogram these cells. Some of these efforts are aimed at understanding and then reversing the stable epigenetics (or gene control) in these cells. We’ve had a lot of opportunities to push on that front in collaboration with experts in the Epigenetics Institute at Penn and our colleagues doing great work with CRISPR gene-editing technology. We’re using concepts of cellular and genome engineering to pick apart the internal wiring of exhausted T cells, and then use what we’ve learned to induce or build better T cells. We’re also excited to understand more about how these T cell exhaustion targeting therapeutics like checkpoint blockades work in people.
Elsewhere at Penn, we’re seeing work on how other parts of the immune system play a role in T cell exhaustion. We’re learning from Andy Minn’s lab about chronic inflammation as a contributor to T cell exhaustion. We’re learning from Carl June and others in the CAR T cell space about genes and pathways that could be targeted to avoid or overcome exhaustion. Other work from June’s group has used receptors that respond to certain growth factors to try to keep T cells from becoming exhausted.
There’s work at Penn that spans the whole spectrum, from the basic fundamental science of how one cell type becomes another, or becomes permanent in its identity, all the way to very clinically applied aspects of avoiding, reversing and understanding exhaustion in T cells that are active in the human body.
Why is Penn a hotbed for T cell exhaustion work?
At Penn, fundamental basic science can be done in a patient receiving one of the most advanced treatments we can imagine. For instance, we can study the exact wiring of the T cells in a tumor in a patient receiving checkpoint blockade molecules. Or in a first-in-humans, CRISPR-engineered trial from June’s group, we can remove one of those checkpoints from the patient’s CAR T cells.
This is the soul of Penn’s scientific enterprise. You never have to explain why we should do scientific analysis in a patient. There’s a clear feeling at Penn that with every patient treated, there’s an opportunity (and almost obligation) to learn, and clinicians and researchers at Penn thrive on this generation of new knowledge that will help improve current treatments and develop new ones. That makes Penn ground zero for not only translating great basic science into patients, but doing fundamental discovery in a patient being treated with an innovative drug.
An Age of Immunotherapies: Related Stories
Building on the Body’s Wisdom: Treatments that manipulate or repair the immune system are becoming more commonplace.
Life, Gained: Walter Styer has cherished 11 years of life after being one of the earliest patients in a trial of the first CAR T cell therapy developed at Penn Medicine.
CAR T for Solid Tumors: Scientists are still learning how to help CAR T cells evade the body’s defenses so they can effectively treat cancers in the breast, brain, lungs, pancreas, and other organs.
Cancer Interception: Cancer vaccines are a form of immune therapy under investigation at Penn, part of a growing effort to intercept cancer before abnormal cells become malignant. (From the Spring 2023 issue of Penn Medicine magazine)
The Immunotherapy Revolution for Autoimmune Diseases: With a deeper understanding of the immune system, there are growing possibilities to selectively turn down only the parts that malfunction—with hopes to someday cure these conditions.