Breakthrough in Pancreatic Cancer Treatment: Taiwan's NHRI Finds New Target to Reverse Immune 'Brake'

(CNA, Taipei, 18th) The effectiveness of current immunotherapy for pancreatic cancer is limited. Taiwan's National Health Research Institutes (NHRI) have confirmed that the MAP4K2 protein kinase is a key 'brake' in the immune response. By simply inhibiting this brake, the vitality of the cancer-killing army can be restored. Efficacy in mouse models has been significant, and it is hoped this will become a new target for pancreatic cancer immunotherapy. Cancer is the leading cause of death in Taiwan. Although pancreatic cancer ranks 7th in cancer-related deaths, it is known as the 'king of cancers' mainly because it is difficult to detect early. Nearly 90% of newly diagnosed patients are in the late stage, and current treatments are very limited, leading to an average 5-year survival rate of less than 10% for pancreatic cancer patients. After 13 years of long-term research, the National Health Research Institutes discovered that inhibiting the key molecule that down-regulates the immune response, 'MAP4K2 protein kinase,' can increase the cytotoxic T lymphocytes responsible for clearing cancer cells, significantly enhancing the anti-pancreatic cancer immune response of immune checkpoint inhibitors. The research findings were published in the international medical journal 'Journal of Clinical Investigation' in March this year. This research is the result of the team of Distinguished Investigator Tan Zse-hwa and Associate Investigator Chuang Huai-chia from the NHRI's Immunology Research Center. At a press conference today, Chuang Huai-chia explained that the immune system is in a delicate balance, normally able to clear infectious agents and harmful substances, and even eliminate cancer cells. Cytotoxic T cells are the main 'force' in the immune system used to destroy cancer cells. Chuang said that when cancer cells can continue to grow and form cancer, it means they have activated a special immune escape mechanism. This mechanism recruits regulatory T cells, which act as a 'braking system,' to the cancer tissue, inhibiting the activity of cytotoxic T cells and preventing them from working properly. This allows cancer cells to successfully evade the immune system's attack and develop into cancer. Chuang stated that immune checkpoint inhibitor drugs are a new direction in cancer treatment, but unfortunately, current immunotherapies are not effective for pancreatic cancer patients. The research team hopes to improve the effectiveness of immune checkpoint inhibitor drugs, and MAP4K2 protein kinase may be the solution. Chuang said that mouse experiments confirmed that MAP4K2 protein kinase promotes and differentiates regulatory T cells in the body; without MAP4K2 protein kinase, there would be no regulatory T cells. Further analysis of single-cell RNA sequencing of pancreatic cancer patient tissues showed that the more severe the pancreatic cancer, the higher the expression of MAP4K2 protein kinase, the more regulatory T cells, and the fewer cytotoxic T cells, allowing cancer cells to grow continuously. The research team further knocked out the MAP4K2 gene in regulatory T cells and conducted immunotherapy in a pancreatic cancer mouse model with a competent immune system. The number of regulatory T cells in the tumor tissue decreased, while cytotoxic T cells increased, significantly enhancing the anti-pancreatic cancer immune response. The researchers combined anti-PD1 immunotherapy with a small molecule inhibitor of MAP4K2 protein kinase and achieved significant efficacy in the pancreatic cancer mouse model. Tan Zse-hwa said that MAP4K2 protein kinase plays a key role in down-regulating the immune response and can serve as a new target in immunotherapy. Developing therapeutic strategies to inhibit MAP4K2 protein kinase, or combining them with existing cancer immunotherapies, will open up new ways of thinking for cancer immunotherapy. (Edited by Kuan Chung-wei)