2019/02/28
Keio University School of Medicine
A group led by Professor Akihiko Yoshimura of the Department of Microbiology and Immunology, Keio University School of Medicine, and Professor Anjana Rao of the La Jolla Institute for Immunology in the United States has elucidated the molecular mechanism that causes exhaustion in immune cells (T-cells) within tumors using a mouse model. They have demonstrated that inhibiting this mechanism can be applied to more effective cancer treatments.
In recent years, cancer immunotherapies such as Opdivo (anti-PD-1 antibody) have been gaining attention. Immune checkpoints are systems, primarily expressed on T-cells, that suppress excessive immune responses. Anti-PD-1 antibodies inhibit these immune checkpoints, enhancing T-cell activation and thereby strengthening their ability to attack cancer. However, it is known that many of the T-cells that accumulate in cancer tissue become dysfunctional, a state known as "exhaustion," due to repeated stimulation, which causes them to highly express multiple immune checkpoint molecules. It is believed that T-cells that have become completely exhausted can no longer be reactivated by anti-PD-1 antibodies, significantly compromising the effectiveness of cancer immunotherapy.
Until now, the molecular mechanism that causes T-cell exhaustion was completely unknown. The research group focused on a transcription factor called Nr4a, which is specifically expressed during exhaustion. The group has now discovered that Nr4a binds to a region of the PD-1 gene called an enhancer, increasing and stabilizing PD-1 expression. By deleting the Nr4a gene, T-cells remained activated for a longer period without becoming exhausted. Furthermore, while all mice in a tumor model died from cancer within 90 days after being administered wild-type T-cells, over 70% of those administered Nr4a-deficient T-cells survived. This revealed that the transcription factor Nr4a plays a central role in the "exhaustion" of T-cells accumulating in tumors and is critically important for anti-tumor effects. The development of Nr4a inhibitors is expected to lead to more effective cancer immunotherapies.
The results of this research were published in the online advance edition of the British scientific journal "Nature" on February 27, 2019 (Greenwich Mean Time).
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