The problem is especially important for checkpoint inhibitors, immunotherapy drugs that remove biological constraints that normally limit T-cell activity.

“The tragic part of T-cell exhaustion is that immunotherapy may seem to be working for a patient, but then the effect wears off,” says Santosha Vardhana, MD, a physician-scientist at Memorial Sloan Kettering Cancer Center (MSK) who treats patients with lymphoma. “Many of them experience only fleeting promise before it is taken away from them.”

Researchers in Dr. Vardhana’s laboratory have identified the signaling molecule MEK as a key factor in this process. Based on animal research published in Immunity, the study suggests that blocking MEK may slow T-cell exhaustion and make some forms of immunotherapy more effective.

“We are excited to apply this discovery to enhance multiple forms of immunotherapy,” Dr. Vardhana says. “Since FDA-approved MEK inhibitors are already available, this approach could be tested in humans without too much delay.”

How MEK Drives T Cells Toward Exhaustion

Scientists are still learning how T cells become exhausted. In 2020, Dr. Vardhana’s laboratory identified an important part of the cellular metabolism puzzle. Metabolism refers to the chemical processes cells use to convert nutrients into energy.

When T cells are continuously exposed to tumor antigens—cancer proteins that the immune system recognizes as foreign—the mitochondria inside the cells can become overburdened. Mitochondria convert nutrients into usable energy for cells.

“There is a huge metabolic demand placed on T cells as they encounter cancer cells and try to produce cancer-killing, or cytotoxic, proteins,” Dr. Vardhana says. “We found that the decision to produce high levels of these proteins is controlled by MEK.”

Overactive MEK signaling can eventually cause T cells to become terminally exhausted, a state of severe exhaustion in which the cells cannot be effectively reactivated by immunotherapy.

“We realized that T-cell exhaustion is not just a loss of function; it reflects an imbalance between what is asked of these cells and the energy available to them,” says Tammana Mitra, a student in Dr. Vardhana’s laboratory and the study’s lead author.

Surprisingly, the researchers found that exhausted T cells were not metabolically inactive. In fact, they remained highly active. When researchers treated the cells with MEK inhibitors, the T cells proliferated more while using more energy.

“That discrepancy made us wonder where that energy goes, and we found that these cells invest enormous resources to make proteins,” Dr. Mitra explains. “It changed the way we thought about T-cell exhaustion. It went from a problem of too little energy to a problem of too much energy demand.”

MEK Inhibition May Help T Cells Conserve Energy

The findings suggest that reducing MEK signaling may reduce the pressure on T cells to continuously manufacture cytotoxic proteins. As a result, some T cells may remain active and capable of self-renewal 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 start to finish. Reducing your intensity can conserve enough fuel to keep going.

In laboratory models, blocking MEK signaling allowed T cells to persist under the difficult conditions found around tumors. However, the researchers caution that MEK inhibition is unlikely to be the right approach for every patient with cancer.

T-Cell Exhaustion May Also Protect Immune Cells

Scientists now understand that T-cell exhaustion is more complex than simply losing immune strength. MSK immunologist Andrea Sittinger previously discovered that T cells can enter an exhausted state as a survival mechanism. By reducing their activity, the cells may avoid overstimulation and death.

“As we learn more about T-cell exhaustion, we increasingly understand that exhausted T cells are not all bad, so we cannot simply use drugs to reverse the process,” Dr. Vardhana says. “Rather, exhaustion is an equilibrium state in which cells survive and continue to function. It’s almost like a ‘safe mode’ for T cells.”

When T cells actively attack cancer and produce cytotoxic proteins, their mitochondria must convert nutrients into adenosine triphosphate, or ATP. ATP is a molecule cells use primarily to store and transfer energy.

“Think of ATP as the currency your cells spend,” Dr. Vardhana says. “When you spend ATP on one thing, you don’t have enough money to do anything else. The exhaustion program is a sign that a cell’s bank account is nearing zero. MEK tells exhausted cells to conserve fuel or go penniless. What we found is that inhibiting MEK makes cells more conservative and can extend their lifespan while slowing down the rate at which they produce proteins that actually kill cancer cells.”

MEK may therefore be both part of the problem and part of the solution. Strong MEK activity helps T cells attack with maximum intensity, but it can also cause them to burn out completely. Blocking MEK may make the immune attack less intense while helping cancer-fighting T cells survive longer.

Whether a short, powerful immune response or a slower, longer-lasting response is preferable may depend on the characteristics of an individual patient’s cancer.

When T Cells May Need to Work at Full Speed

According to Dr. Vardhana, MEK inhibitors should be used selectively. Two factors may indicate that a patient is likely to respond well to immunotherapy:

1. The tumor is small.
2. The patient has large numbers of immune cells that can attack the tumor, often because the tumor has many mutations that make it easier for the immune system to recognize.

“T-cell preservation is less important in these patients,” Dr. Vardhana says. “It’s like being in a car with one-eighth of the tank left, but the finish line is in sight. For these patients, all you have to do is keep the car burning gas. In other words, you’re taking a traditional immunotherapy approach. These patients probably don’t need MEK inhibition.”

The situation may be different for patients with larger tumors or fewer tumor-fighting immune cells. Their immune response may not be strong enough to eliminate the cancer quickly.

In these cases, a slower and more sustained response supported by MEK inhibition may allow T cells to persist longer, even if they are partially exhausted. This persistence may be particularly important when the tumor is large or the number of cancer-fighting T cells is small.

Potential Applications in Cancer Immunotherapy

Dr. Vardhana says that carefully applied MEK inhibition could improve several types of immunotherapy.

Checkpoint Inhibitors

MEK inhibitors may be combined with checkpoint inhibitors and BRAF inhibitors as part of a broader treatment strategy.

CAR T-Cell Therapy

“We believe this approach can dramatically increase T-cell persistence, which has been a major issue with CAR T-cell therapy,” Dr. Vardhana says.

Tumor-Infiltrating Lymphocyte Therapy

Tumor-infiltrating lymphocyte, or TIL, therapy uses immune cells that are already attacking a patient’s cancer and increases their numbers. Using MEK inhibition before and after TIL therapy may allow the most effective tumor-fighting T cells to survive longer.

Bispecific Antibodies

Bispecific antibodies are laboratory-made proteins designed to bind to two different targets at the same time. These therapies can strongly activate T cells, but intense stimulation may also contribute to T-cell exhaustion.

“This study shows the importance of understanding the core principles of T-cell biology, which determine the balance between energy conservation and powerful cancer-fighting activity,” Dr. Vardhana says. “Once we know the answer, the possibilities for treatment will really expand.”

Key Findings

• Repeatedly recognizing and attacking cancer can cause T cells to become exhausted and less able to control tumors.
• The signaling molecule MEK appears to play an important role in directing T cells toward exhaustion.
• Blocking MEK reduces cellular energy demands, potentially allowing T cells to survive longer during cancer treatment.
• MEK inhibition may be especially useful for patients who do not respond well to traditional immunotherapy, including those with large tumors or relatively few immune cells capable of recognizing cancer.

Other authors of 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.