Pancreatic cancer is particularly treacherous: the tumor forms a dense, fibrous layer of connective tissue that surrounds it like a protective shield. This makes it more difficult for both medications and immune cells to reach the tumor. Now, a research team at the University of Zurich has developed a novel vaccine that specifically targets these fibrous structures in the tumor environment, offering new hope for treatment.
Pancreatic cancer is one of the deadliest cancers in Switzerland, with around 1,400 deaths per year. Despite medical advances, the prognosis remains poor: about 87 percent of patients die within five years of diagnosis. One of the main reasons for this is the high resistance of this tumor type to existing therapies—largely due to its unique, well-shielded structure.
A key characteristic of pancreatic cancer is fibrosis, an abnormal overgrowth of dense connective tissue around the tumor. This hardening acts like an internal scar. It impairs blood flow and prevents immune cells and medications from effectively reaching and attacking the cancer cells. Fibrosis is mainly caused by cancer-associated fibroblasts (CAFs). Fibroblasts are connective tissue cells that produce important components like proteins (e.g., collagen), providing stability and structure to tissue. In the tumor environment, however, CAFs not only promote tumor growth but also therapy resistance and metastasis.
Despite their key role in the tumor environment, there are currently very few targeted therapies against CAFs. Existing treatments mostly focus on the tumor cells themselves. This is where the research project led by Professor Christian Stockmann at the Institute of Anatomy, University of Zurich, comes in. The team has developed an immunotherapeutic vaccine that specifically targets a protein called ADAM12, which is mainly found in activated fibroblasts—precisely the cells responsible for forming the fibrotic protective layer. The researchers aimed to activate the immune system through the vaccine to recognize, attack, and destroy the CAFs without damaging healthy tissue.
In several mouse models, the vaccine showed a clear therapeutic effect: tumors grew more slowly and remained significantly smaller. The number of CAFs causing fibrosis decreased, along with the amount of dense connective tissue around the tumor. Additionally, the number of certain immune cell types in the tumor environment changed: inflammatory immune cells decreased, while specific subtypes of T cells increased. Detailed analyses of the tumor tissue also showed increased activity of these T cell subtypes against tumor cells expressing ADAM12 on their surface. This suggests that the vaccine triggered a targeted immune response against the tumor.
A frequently discussed risk when destroying fibroblasts is that healthy tissue—such as important support cells in blood vessels—might be unintentionally affected. This could worsen oxygen supply and even promote tumor growth. However, the opposite was observed: the vaccine improved blood vessel structure and reduced oxygen deficiency in the tumor. As a result, the aggressiveness of tumor cells decreased, and liver metastases occurred less frequently.
In the next step, the researchers aimed, through a combined approach, to make the tumor environment more receptive to conventional therapies by using the vaccine. Previous studies have already shown that reducing the dense connective tissue in tumors improves blood flow, thereby increasing the effectiveness of chemotherapy.
Indeed, the vaccine improved tumor blood flow to such an extent that the chemotherapy drug could distribute more effectively. Compared to chemotherapy alone, tumor cell destruction was significantly greater, and the number of rapidly growing tumor cells decreased. But the vaccine didn’t just enhance chemotherapy effectiveness. Early results combining the vaccine with immunotherapies suggest it may also improve the success of these treatments.
These findings offer hope and open a new therapeutic perspective for patients with pancreatic cancer, for whom effective treatment options have been scarce. The vaccine targeting CAFs could potentially make tumors less aggressive and more accessible to chemo- and immunotherapies in the future.
Next, the researchers plan to extend their investigations to other cancers with fibrotic tumor environments, such as liver, stomach, esophageal, colorectal, and cervical cancers. They also aim to further explore which fibroblast subtypes are particularly relevant to tumor progression. All these insights will support the preparation of clinical trials to evaluate the vaccine’s safety and effectiveness in humans.
Project number: KFS-5402-08-2021
Publication:
Chen J., Sobecki M., Krzywinska E., Thierry K., Masmoudi M., Nagarajan S., Fan Z., He J., Ferapontova I., Nelius E., Seehusen F., Gotthardt D., Takeda N., Sommer L., Sexl V., Münz C., DeNardo D., Hennino A., Stockmann C.: „Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas.“ EMBO Mol Med. 2024 Dec;16(12):3033-3056. https://doi.org/10.1038/s44321-024-00157-4
| This project received funding from Swiss Cancer Research in collaboration with six other foundations. We would especially like to acknowledge the Anne and Peter Casari-Stierlin Foundation, the Schwab Seubert Foundation and the Werner Geissberger Foundation. |
