When faced with long-lasting challenges, such as cancer or persistent infections that the immune system struggles to clear, T cells of the adaptive immune system can become exhausted. The exhausted cells lose function, diminishing both the immediate immune response and the ability to form immune memory that will enable a robust future response to the same threat. Researchers see this in the engineered T cells used in chimeric antigen receptor (CAR) T cell therapies, and there is thus a strong incentive to find ways to address the issue by identifying important causes or regulators of T cell exhaustion, and interfering to prevent it.
Fighting a tumor is a marathon, not a sprint. For cancer-fighting T cells, the race is sometimes just too long, and the T cells quit fighting. Researchers even have a name for this phenomenon: T cell exhaustion. Researchers now report that T cells can be engineered to clear tumors without succumbing to T cell exhaustion. This research builds on work that has shown the key role of proteins called transcription factors in the cellular pathway that triggers T cell exhaustion. This work is important because T cell exhaustion continues to plague even the most cutting-edge cancer immunotherapies.
With CAR T therapies, for example, researchers take T cells from a cancer patient and "arm" them by altering the expression of genes that aid in the cancer fight. Researchers make more of these special T cells, which then go back into the patient. CAR T therapies are different from immunotherapies, which aim to activate the patient's existing T cell population. With both approaches, T cell exhaustion rears its ugly head. "Many people have tried to use CAR T therapies to kill solid tumors, but it's been impossible because the T cells become exhausted."
The new study addresses this problem by giving T cells the ability to fight exhaustion itself. To accomplish this, the researchers screened T cells to uncover which transcription factors could boost a T cell's "effector" program, an important step in readying T cells to kill cancer cells. This screening process led the researchers to BATF, a transcription factor that they found cooperates with another transcription factor called IRF4 to counter the T cell exhaustion program.
In mouse melanoma and colorectal carcinoma tumor models, altering CAR T cells to also overexpress BATF led to tumor clearance without prompting T cell exhaustion. The CAR T therapy worked against solid tumors. Encouragingly, some altered T cells also stuck around and became memory T cells. This is important because T cell exhaustion often prevents T cells from mounting a strong memory response to recurrent cancers.