T Cell Exhaustion and Cancer Immunotherapy

In the presence of persistent virus or cancer, CD8 T cells lose much of their ability to fight disease and display inhibitory checkpoint proteins such as PD-1 on their surfaces. In a study published yesterday in Immunity, Emory scientists investigated what makes T cells “exhausted” and how this knowledge could be used to refine cancer immunotherapy.

PD-1 is targeted by cancer immunotherapy drugs, such as pembrolizumab and nivolumab, which allow CD8 T cells to regain their ability to attack and kill infected cells and cancers. Drugs like these are now FDA-approved for several types of cancer, yet some types of tumors do not respond to them. Studying exhausted CD8 T cells can help us understand how to better draw the immune system into action against cancer or chronic infections.

In previous research, the team found that exhausted cells are not all alike and that the diversity within the exhausted T cell pool could explain variability in responses to cancer immunotherapy drugs. Specifically, they observed that a population of stem-like cells proliferated in response to PD-1-blocking drugs, while a more differentiated population of exhausted cells stayed inactive. The stem-like cells are responsible for maintaining the exhausted T cell population but cannot kill virus-infected or tumor cells on their own.

The current paper defines a transitional stage in between the stem-like and truly exhausted cells. The truly exhausted cells are marked by a molecule called CD101, are unable to migrate to sites of infection, and contain lower amounts of the proteins needed to kill infected or tumor cells.

“The transitional cells are not completely exhausted,” says first author Will Hudson. “They are still capable of proliferating and performing their ‘killer cell’ functions. In our experiments, they contribute to viral control.”

The transitional cells, lacking CD101, could be a good marker for response to PD-1-blocking drugs, Hudson says. Enhancing the proliferation or survival of these cells, or preventing their transition to lasting exhaustion, may be a novel therapeutic strategy for cancer.

The study also includes systematic identification of other markers for CD8 T cells in various stages of exhaustion, which could be a guide to efforts to promote their activity.