[Life] NTU Discovers New Mechanism for Lung Cancer Immunotherapy That Can Awaken Exhausted T Cells

Lung cancer is the leading cause of cancer death. T cells are important soldiers in killing cancer cells, but the tumor microenvironment can lead to their functional exhaustion. National Taiwan University Hospital has discovered a new mechanism to reactivate terminally exhausted T cells, restoring anti-tumor capabilities and helping to improve the effectiveness of cancer immunotherapy. Lung cancer has been the leading cause of cancer death in Taiwan since 2004. Dr. Tsai Hsing-chen, associate director of NTU Hospital's Center for Advanced Medical Development and attending physician in the Department of Thoracic Medicine, said at a press conference today (16th) that this phenomenon is related to over 40% of patients being diagnosed at an advanced stage. Treatment options for advanced lung cancer include chemotherapy, targeted therapy, radiation therapy, and immunotherapy. T cells are the core fighting force of the immune system in recognizing and eliminating cancer cells. Long-term stimulation by tumors leads them into an exhausted state, gradually losing their proliferative and cytotoxic abilities. Cancer immunotherapy's "immune checkpoint inhibitors" can activate T cells and have been used in the treatment of various cancers in recent years, but some still develop resistance. In particular, terminally exhausted T cells are almost impossible to reactivate, which is also a bottleneck in the treatment of advanced lung cancer patients. The research team at NTU Hospital used exhausted T cells from lung cancer patients for large-scale drug screening and successfully discovered a class of epigenetic drugs called "BET inhibitors." These inhibitors can enhance the plasticity of terminally exhausted T cells, restore their function, and improve anti-tumor activity. Studies have shown that BET inhibitors reactivate terminally exhausted T cells by increasing polyamine content within T cells to regulate immune metabolic status. Dr. Tsai said that after the research team inhibited key proteins in the polyamine biosynthesis pathway through gene editing or drugs, the immune-enhancing effect produced by BET inhibitors completely disappeared. This indicates that polyamine biosynthesis plays an indispensable core role in T cell reactivation and may even have the opportunity to reshape the fate of exhausted T cells, maintain their long-term anti-cancer ability, and enhance the sustained effect of immunotherapy. Dr. Tsai stated that in lung cancer mouse models, both direct treatment with BET inhibitors and adoptive cell therapy with T cells treated with BET inhibitors significantly inhibited tumor growth. This study is the first to reveal the key mechanism of epigenetic regulation and the remodeling of T cell metabolic status. It was published in the international journal "Nature Immunology" in May of this year. Dr. Tsai said that this achievement in overcoming the treatment limitations caused by terminal T cell exhaustion not only provides a new strategy for lung cancer treatment but also has the potential to be extended to other solid tumors that respond poorly to immunotherapy. In the future, it may be combined with existing immune checkpoint inhibitors, CAR-T cell therapy, and other cell therapy technologies to develop more effective next-generation cancer immunotherapy strategies. (Editor: Shen Chen-chiang)