New research has revealed the role that basic leucine zipper ATF-like transcription factor (BATF) plays in the cell pathway that leads to T cell exhaustion, where cancer-fighting T cells stop attacking cancer cells following a prolonged period of overactivity.
T cell exhaustion is a problem with all cancer immunotherapies. While the treatments are initially effective and the T cells target cancer cells, the fight can prove to be too long and the T cells succumb to exhaustion and simply stop attacking the cancer cells.
Researchers at La Jolla Institute for Immunology (LJI) were looking for a way to protect T cells to combat the exhaustion problem and help them carry on for longer. The researchers demonstrated that by increasing the level of BATF in the cells, along with the level of transcription factor IRF4, the cancer-fighting ability of the T cells was improved.
This approach could be used in CAR T cell-based immunotherapy for treating tumors. CAR T immunotherapies involve harvesting T cells from a cancer patient, then altering gene expression in the lab to arm them in the fight against cancer. The cells are then replicated in the lab and reintroduced into the patient. Other types of immunotherapies attempt to activate the existing T cell population in patients to get them to attack the cancer cells, but T cell exhaustion is a problem in both treatment approaches.
T cell exhaustion stops immunotherapies from being effective at treating solid tumors, as the prolonged antigen stimulation results in the T cells entering a hyporesponsive state where they are no longer effective at destroying cancer cells.
The researchers screened T cells to identify transcription factors that were able to boost the effector program of T cells, which is an important process in preparing the cells to target cancer cells. The researchers identified the transcription factor BATF and determined that it cooperates with another transcription factor called IRF4, which counter T cell exhaustion
“The anticancer effects were dependent on BATF–IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth,” explained the researchers. The researchers determined overexpression of BATF to around 20 times normal levels were optimal, and while interaction with transcription factor IRF4 is important, the researchers determined it is not necessary to overexpress IRF4 to the same degree as BATF.
The researchers demonstrated in mouse melanoma and colorectal carcinoma tumor models, changing CAR T cells to overexpress BATF allowed the T cells to clear a tumor without the T cells succumbing to exhaustion. The researchers also found that some of the T cells became memory T cells.
“Some BATF-transduced CAR T cells remain after tumor clearance as memory-like cells that are fully capable of making a subsequent antitumor response,” explained the researchers. “Thus, BATF overexpression corrects the two cardinal features of T cell exhaustion: the immediate limitation on effector function and the long-term limitation on memory formation.” So, the researchers not only engineered T cells to fight exhaustion, they were also able to improve their tumor fighting ability.
You can read more about the study in the paper – BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells – which was recently published in Nature Immunology. DOI: 10.1038/s41590-021-00964-8
Image: Healthy Human T Cell. Source: National Institute of Allergy and Infectious Diseases