A research team from the National Health Research Institutes has found a way to make immunotherapy more effective against pancreatic cancer: blocking MAP4K2, a protein kinase that appears to weaken the effect of anti-PD-1 treatment.
Pancreatic cancer is widely known as the “king of cancers,” as it is extremely difficult to detect early, and about 90 percent of cases are diagnosed late, resulting in low survival rates of 5 to 10 percent, the research team said at a news conference at the Ministry of Health and Welfare in Taipei yesterday.
Immune checkpoint inhibitors, such as anti-PD-1 therapy, have shown very limited efficacy in treating pancreatic cancer, with an objective response rate of only about 20 to 30 percent, so there is an urgent need to develop strategies to enhance immunotherapy, the team said.
Photo: CNA
A delicate balance exists in the immune system, which under normal conditions can defend against infectious pathogens, remove harmful substances and even eliminate cancer cells, said Chuang Huai-chia (莊懷佳), associate investigator at the institute’s Immunology Research Center.
Cytotoxic T cells serve as the primary “military force” in the immune system and destroy cancer cells, but when cancer cells grow into tumors, it means they have activated a special “immune evasion” mechanism, recruiting regulatory T cells and suppressing the activity of cytotoxic T cells, she said.
Immunotherapy reawakens the body’s cytotoxic T lymphocytes, which are responsible for eliminating cancer cells, she said, adding that anti-PD-1 therapy has shown limited efficacy against pancreatic solid tumors.
After 13 years of research, the team developed genetically engineered mice with the MAP4K2 gene deleted, and their latest findings reveal that MAP4K2 promotes the generation of regulatory T cells.
Researchers further analyzed tumor tissues from people with pancreatic cancer, and they found that more severe cases exhibited higher levels of MAP4K2 and a greater number of regulatory T cells, while cytotoxic T cells were reduced, meaning that the cancer cells built a “shield,” Chuang said.
After selectively knocking out the MAP4K2 gene in regulatory T cells, researchers tested anti-PD-1 therapy on mice with pancreatic cancer and healthy immune systems, she said.
They observed a decrease in regulatory T cells within the tumor tissues and an increase in tumor-attacking cytotoxic T cells, significantly enhancing immune response to pancreatic cancer, she said.
Furthermore, combining anti-PD-1 therapy with a small molecule inhibitor targeting MAP4K2 yielded significant therapeutic efficacy in mice with pancreatic cancer, she added.
Research findings were published in The Journal of Clinical Investigation in March, the institute said.
The research team believes MAP4K2 has the potential to become a new target for cancer immunotherapy, offering a new therapeutic direction, said Tan Tse-hua (譚澤華), distinguished investigator of the institute’s Immunology Research Center.
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