Cancer immunotherapy can unleash T cells, the immune system’s specialized cancer killers, against tumors. But there is a major limitation: These cells can become worn down before the cancer is eliminated. This condition, known as T cell exhaustion, leaves the cells unable to maintain a strong attack or keep tumor growth under control.
That problem has been particularly important for checkpoint inhibitors, immunotherapy drugs designed to remove biological restraints that normally limit T cell activity.
“A tragic part of T cell exhaustion is that the immunotherapy seems to be working for patients, and then it fades,” says Santosha Vardhana, MD, PhD, a physician-scientist at Memorial Sloan Kettering Cancer Center (MSK) who treats people with lymphoma. “Many of them experience a brief wisp of promise only to have it taken away.”
Researchers in Dr. Vardhana’s laboratory have now identified a signaling molecule called MEK as an important driver of this exhaustion process. Based on animal studies published in Immunity, the findings suggest that blocking MEK might slow T cell exhaustion and potentially make immunotherapy more effective.
“We’re excited about applying this finding to enhance multiple forms of immunotherapy,” Dr. Vardhana says. “FDA-approved MEK inhibitors are already available, so this approach could be tested in humans without much delay.”
How MEK Pushes T Cells Toward Exhaustion
Scientists have only recently begun to understand the processes that cause T cells to become exhausted. In 2020, Dr. Vardhana’s laboratory identified an important piece of the puzzle: the cells’ metabolism, meaning the chemical processes they use to turn nutrients into energy.
When T cells are continuously exposed to tumor antigens (the cancer proteins the immune system sees as foreign), the mitochondria inside the cells can become overburdened. Mitochondria are responsible for transforming nutrients into energy that cells can use.
“There is a large metabolic demand being imposed as T cells encounter cancer cells and try to produce cancer-killing, or cytotoxic, proteins,” Dr. Vardhana says. “It turns out that the decision to make high levels of these proteins is regulated by MEK.”
If MEK becomes excessively active, it can eventually drive T cells into terminal exhaustion, a severely depleted state in which immunotherapy can no longer reactivate them.
“We realized T cell exhaustion isn’t simply a loss of function — it reflects an imbalance between what these cells are being asked to do and the energy they have available,” says Tanmana Mitra, PhD, a student in the Vardhana lab and the study’s first author.
Surprisingly, the team discovered that exhausted T cells were not metabolically sluggish. They were actually highly active. When researchers treated the cells with MEK inhibitors, the T cells multiplied more while consuming less energy.
“That paradox made us ask where all that energy was going, and we discovered that these cells were investing enormous resources into making proteins,” Dr. Mitra explains. “It changed how we think about T cell exhaustion — from a problem of too little energy to one of excessive energy demand.”
Helping T Cells Pace Themselves
The findings suggested that reducing MEK signaling could lower the pressure on T cells to continuously manufacture cytotoxic proteins. That, in turn, allowed some of the cells to stay active and capable of renewing themselves for longer, potentially extending the effectiveness of immunotherapy.
The concept is similar to pacing yourself during a long road trip instead of driving at full speed from beginning to end. Reducing the intensity can help preserve enough fuel to keep going.
In laboratory models, blocking MEK signaling allowed T cells to persist even in the difficult conditions surrounding a tumor.
But the researchers caution that suppressing MEK is unlikely to be the right approach for every cancer patient.
T Cell Exhaustion Can Also Be Protective
Scientists now understand that T cell exhaustion is more complicated than simply having immune cells lose their strength. MSK immunologist Andrea Schietinger, PhD, previously found that T cells can enter an exhausted state as a survival mechanism. By reducing their activity, they avoid becoming overstimulated and dying.
“As we’ve learned more about T cell exhaustion,” Dr. Vardhana says, “we’ve increasingly understood that it’s not the case that exhausted T cells are bad, so let’s try to reverse the process with a drug. Instead, exhaustion is more of an equilibrium state that lets the cells survive and keep going — almost like a ‘safe mode’ for T cells.”
When a T cell is actively attacking cancer and producing cytoxic proteins, its mitochondria must turn nutrients from food into adenosine triphosphate (ATP). ATP is the molecule cells primarily use to store and transfer energy.
“Think of ATP as the currency in a fund that the cell spends down,” Dr. Vardhana says. “If you spend ATP on one thing, you don’t have enough to do something else. The exhaustion program is a sign that the cell’s bank account is getting close to zero. MEK tells exhausted cells whether to conserve fuel or go for broke. What we found is that inhibiting MEK makes the cells more conservative — helping them live longer while reducing the rate at which they produce the proteins that actually kill cancer cells.”
That makes MEK both part of the problem and part of the solution. Strong MEK activity helps T cells attack at maximum intensity, but it can also push them toward complete burnout. Blocking MEK therefore involves a tradeoff: The immune attack may become less intense, but the cancer-fighting cells can survive longer.
Whether a short, powerful immune response or a slower, longer-lasting one is preferable may depend on the characteristics of an individual patient’s cancer.
When T Cells May Need To Go Full Speed
According to Dr. Vardhana, MEK inhibitors would need to be used selectively. Two factors can indicate that a patient is likely to respond well to immunotherapy:
- The tumors are small.
- The patients have a high number of immune cells attacking the tumor — usually because the tumor has many mutations that make it recognizable.
“In these patients, conservation of T cells is not that important,” he says. “It’s like being in a car with 1/8 of a tank left, but you can see the finish line. In these patients, you would just let the car keep burning the gas — in other words, take the traditional immunotherapy approach. These are the patients in whom MEK inhibition is probably not needed.”
The situation may be different for patients with large tumors or relatively few tumor-fighting immune cells. Their immune response may not be powerful enough to eliminate the cancer quickly.
In those cases, creating a slower, sustained response with a MEK inhibitor could help T cells remain present for longer, even if they are partly exhausted. That persistence may be especially important when either the task at hand (the tumor) is large or the workforce (the number of T cells) is small.
Potential Uses Across Cancer Immunotherapy
Dr. Vardhana says carefully applied MEK inhibition could potentially improve several types of immunotherapy.
Checkpoint inhibitors: MEK inhibition has already shown effectiveness in melanoma when combined with checkpoint inhibitors and a targeted treatment known as a BRAF inhibitor.
Chimeric antigen receptor (CAR) T cell therapy: “We think this approach could dramatically boost T cell persistence, which has been a big problem with CAR T cell therapy,” Dr. Vardhana says.
Tumor infiltrating lymphocyte (TIL) therapy: This treatment takes advantage of immune cells that have already been attacking a patient’s cancer and expands their numbers. Using MEK inhibition before or after TIL therapy could potentially help the most effective tumor-fighting TILs survive longer.
Bispecific antibodies: These laboratory-made proteins are designed to attach to two different targets at the same time. They can strongly activate T cells, but that intense stimulation may also contribute to exhaustion.
“This study shows the importance of understanding core principles of T cell biology — what sets the balance between conservation of energy and strong, cancer-fighting activity,” Dr. Vardhana says. “Once we know the answer to that, the therapeutic possibilities really start to fan out.”
Key Takeaways
- T cells can become exhausted as they continuously recognize and attack cancer, reducing their ability to keep tumors under control.
- The signaling molecule MEK appears to play an important role in pushing T cells toward exhaustion.
- Blocking MEK may slow that process by reducing the cells’ energy demands, potentially helping them persist for longer during cancer treatment.
- The researchers suggest this strategy could be particularly useful for patients who respond poorly to traditional immunotherapy, including those with large tumors or relatively few immune cells capable of recognizing the cancer.
Additional authors on the study include Jahan Rahman, Madeline Hwee, Yan-Ting Chen, Ruben Jose Jesus Faustino Ramos, Hui Liu, Travis Hartman, Justin Cross, Miguel de Jesus, Morgan Huse, Valerie Longo, and Pat Zanzonico.
