Reprogramming of the molecular pathways underlying normal metabolism is essential for T cell infection-fighting function and for the immune system to form a “memory” of the microbes it has already encountered. But exactly how metabolism in exhausted T cells is maintained in chronic infections and cancer is a missing element in this line of research. Now, a new study suggests that tweaking metabolic steps in combination with checkpoint blockade drugs may improve some cancer therapies, according to research from the Perelman School of Medicine at the University of Pennsylvania. The team published their findings in the journal Immunity.

When T cells are activated because of a microbe or a tumor in a host, “they have a lot of work to do. They need to make many copies of themselves by generating building blocks to make new cells,” said senior author E. John Wherry, director of the Institute for Immunology, professor of microbiology and co-director of the Parker Institute for Cancer Immunotherapy at Penn. “T cells have to drastically change their energetic lifestyle, going from a sedentary couch potato existence to being a marathoner in a very short time.”

Physiologically, this transformation entails going from a “catabolic” existence of slow metabolic burn to an “anabolic” one in which the body revs up to generate chemical intermediates to build new cells. But T cells are hard wired to stop the fast lane anabolic mode after a certain time because functioning at that level is unsustainable.

“We found that as early as the first week of a chronic viral infection, even before severe T cell dysfunction becomes established, virus-specific T cells are already unable to match the bioenergetic demands of T cells generated during the height of fighting a well-contained viral infection in a mouse model,” Dr. Wherry said.

D-1, a cell surface receptor and target of widely used cancer drugs, tells T cells to turn off the anabolic pathway, but other molecular signals say keep this pathway turned on because chronic infection or growing tumors are still present. “Now we have metabolically confused T cells,” Wherry said.

Many tumors make proteins that bind with PD-1 to shut down the T cell signal, and drugs that block this process are one of the most prolific areas of cancer research.

Dr. Wherry’s team induced infection in mice using two different strains of the lymphocytic choriomeningitis virus (LCMV), a well-studied model system for exploring T cell biology. In one group of mice, the virus was cleared in a week by healthy, or effector T cells, and in another group the clearance was derailed because T cells became exhausted.

The study identified the timing—earlier than previously thought—of when PD-1 turns off the anabolic metabolism signal. This finding has implications for the clinic because it identifies the altered metabolism as a distinct point in the development of exhausted T cells versus as a later consequence of exhausted T cells.

These findings also identified PD-1’s role as the metabolic switch in shutting down anabolic pathways and characterized downstream metabolic regulator targets of PD-1.

One area on the research horizon, says Dr. Wherry, is to find a way to enhance exhausted T cells by testing drugs that manipulate metabolism. The team will also explore ways to pharmacologically improve mitochondria health.