Researchers have found that using a commonly prescribed chemotherapy drug can enhance the effectiveness of immunotherapy for pancreatic cancer. By utilizing folinic acid, levels of two crucial immune molecules—natural killer T cells and type-I interferons—are increased within pancreatic tumors. In studies involving mice, this resulted in a stronger immune response, reduced tumor growth, and improved survival rates.
Cold Spring Harbor Laboratory Professor Douglas Fearon has uncovered that utilizing a familiar chemotherapy drug can significantly boost the efficacy of immunotherapy for pancreatic cancer. Folinic acid increases the concentrations of two vital anti-cancer immune molecules, namely natural killer T cells and type-I interferons, in pancreatic tumors. In mouse models, this enhancement lead to a more robust immune reaction, slower tumor development, and extended survival.
The battle against cancer resembles an ongoing arms race, wherein one of the most potent tools at clinicians’ disposal is immunotherapy. Immune checkpoint therapy has emerged as a leading treatment for various cancer types. Nonetheless, this Nobel Prize-winning approach often falls short for the majority of patients suffering from pancreatic ductal adenocarcinoma (PDAC).
According to Professor Douglas Fearon from Cold Spring Harbor Laboratory (CSHL), “Immune checkpoint therapy is only viable in a small number of PDAC cases. It is effective exclusively for the specific subtype of PDAC, accounting for less than 5% of cases.”
Historically, it was believed that PDAC did not elicit any immune response. However, in 2023, Fearon and his research team demonstrated that immune cells do indeed engage in combat. Unfortunately, these cells face challenges penetrating the aggressive tumors, enabling PDAC to persist. Recent findings from Fearon and former CSHL postdoc Jiayun Li revealed that a widely used chemotherapy adjunct, folinic acid, compromises the cancer’s defenses in mice. Their research indicated that folinic acid enhances the levels of two anti-cancer immune molecules in PDAC: natural killer T (NKT) cells and type-I interferons, which consequently leads to improved immune responses, slower tumor progression, and better survival outcomes.
Fearon explained, “We found that NKT cells help produce type-I interferon, which in turn facilitates adaptive immune responses and the proliferation of T cells.” These T cells are critical in targeting tumors but often cannot infiltrate them without the presence of type-I interferon. Folinic acid significantly bolsters this immune response.
PDAC effectively shields itself from immune cells by constructing a formidable barrier composed of two proteins—CXCR4 and CXCL12—making it nearly impervious. However, when the team administered folinic acid to PDAC tumors, vulnerabilities emerged. The surge in NKT cells and type-I interferons served as markers, guiding cancer-fighting immune cells that had previously been kept at bay to enter the tumors and engage in combat.
Looking ahead, the Fearon lab is working to transform its findings into new therapeutic options. They have recently collaborated with a biotechnology firm, Autobahn Labs, to create potential treatments aimed at CXCR4 and CXCL12. These advancements could potentially enable immune checkpoint therapy to become a standard approach in the battle against PDAC.
“Converting discoveries from mouse models to human therapies has been a challenge,” Fearon stated. “However, if we succeed, immunotherapy could eventually become a feasible treatment alternative for all patients with PDAC—and other solid tumors—not just a rarity as seen currently.”
