When it comes to cancer therapies, the field is abuzz with enthusiasm for treatments that rely on the patient’s own immune cells.

What are T cells?

Immunotherapies for cancer enlist the body’s own immune system to kill cancer cells. One such therapy, called immune checkpoint blockade, involves patients receiving a drug that reactivates a patient’s T cells, a type of white blood cell trained to recognize and attack viruses and tumors, allowing them to kill virally infected or tumor cells. These tumor-fighting T cells detect a protein, called an antigen, on the cancer cells’ surface that triggers the attack. But sometimes, this therapy is ineffective.

Why do T cells become exhausted?

Our lab studied how exhausted T cells lost their ability to fight cancer cells or viruses in preclinical models. We learned the cause was an epigenetic program that represses the T cell’s ability to respond. Epigenetic controls are molecular switches that turn genes on or off to control the cell’s machinery. In addition, this epigenetic exhaustion switch gets passed on to successive generations of T cells. The stable nature of these programs have important implications regarding the patient’s ability to fight cancer — if he or she comes into the clinic with a tumor, it’s likely they have had it for some time. That means those T cells have been exposed to the tumor antigen for some time, and they’re in an exhausted state.

How can T cells be reactivated?

First, we learned this mechanism for reinforcing exhaustion was intrinsic to the T cells. That means you can pull out the T cells and supercharge them to fight a cancer, and then reintroduce them into a patient. Second, we also learned that a chemotherapy drug showed promise in enhancing T cells in preclinical models. These findings were recently published in the journal Cell, and could prove to be clinically significant.

What does this mean for immunotherapies?

While still very early, our findings suggest that combining therapeutic approaches that induce epigenetic reprogramming with immune checkpoint blockade could enhance cancer treatments. But it could also mean more.

Patients with HIV also suffer T cell exhaustion. These therapies could possibly provide a path to treat HIV and a variety of other chronic viral infections. We’re now looking into these epigenetic programs further to get a basic understanding and learn how to apply this understanding in cancer and other immunotherapies.