Study Identifies Fibroblasts that Shield Pancreatic Cancer from Immune System

Researchers in Texas have identified a subset of cancer-associated fibroblasts (CAFs) that shield pancreatic cancer cells from immunotherapy. The findings, published in the journal Cancer Cell, could offer a new strategy to fight pancreatic cancer, a deadly disease for which no truly effective treatments exist.

According to the American Cancer Society, about 56,000 people in the United States are diagnosed each year with pancreatic ductal adenocarcinoma (PDA), the most common form of pancreatic cancer. Currently the fourth-leading cause of cancer-related deaths in the country, it’s projected to become the second-leading cause by 2030. Despite decades of research, the prognosis for PDA remains poor, with only 10% of patients surviving five years past diagnosis.

Researchers have long known that CAFs make up a significant portion of pancreatic tumors. Much like the fibroblasts that compose scar tissue, CAFs make pancreatic tumors dense and tough, preventing chemotherapies and other treatments from readily reaching cancer cells.

Scientists had considered pancreatic CAFs to be a uniform population until Huocong Huang, M.D., Ph.D., Instructor of Surgery at University of Texas Southwestern (UTSW) and colleagues showed in 2019 that the cells are comprised of three subtypes. One of the subtypes—antigen-presenting CAFs (apCAFs)—interact with immune cells by displaying proteins called antigens on their surface. “By targeting antigen-presenting cancer-associated fibroblasts, we might someday be able significantly to enhance the activity of immune therapy in pancreatic cancer patients,” Huang says.

To determine how apCAFs contribute to PDA progression, Dr. Huang and colleagues used a technique known as lineage tracing to learn how these cells arise as a normal pancreas develops cancer. Their findings showed that apCAFs originate from mesothelial cells, which form a protective membrane that lines organs, body cavities, and tissues.

Further experiments showed that the antigens on the surface of apCAFs could convert immune cells called T-cells into a subset known as regulatory T-cells (Tregs), which shield tumors from immune attack. When the researchers dosed mice carrying pancreatic tumors with antibodies against mesothelin, a protein unique to mesothelial cells, the conversion to Tregs was blocked, leaving tumors more vulnerable to an anti-tumor immune response.

Although more research is necessary in animal models, Dr. Huang noted that it may eventually be possible to employ a similar strategy to treat PDA in humans by administering anti-mesothelin antibodies in combination with immunotherapies that stimulate the immune system to fight cancers.