New research in mice has shed light on how antibodies could be harnessed to puncture the shield of scarlike cells that protect pancreatic cancer from treatment.
The knowledge that cells called cancer-associated fibroblasts (CAFs) make up a significant portion of pancreatic tumors is nothing new. These scarlike cells can make tumors dense and tough, blocking chemotherapies and other anti-cancer treatments from reaching the cancer cells.
Previous research by Huocong Huang, M.D., Ph.D. and others at the University of Texas Southwestern Medical Center had already revealed that these CAFs fell into three groups, one known as antigen-presenting CAFs (apCAFS).
By using RNA sequencing studies and lineage tracing assays in mice models, the researchers have now shown that these apCAFs are derived from mesothelial cells, which normally form protective membranes around the organs, body cavities and tissues. Many of the biological processes they identified in the creation of apCAFs were related to the wounding or inflammatory response, suggesting that a wound-associated signal from the tumor can trigger the creation of these cells.
What’s more, antigens on the surface of apCAFs can convert immune cells, called T cells, into a subset known as regulatory T cells (Tregs), which also shield tumors from immune attack, the researchers said.
Injecting tumor cells from mice with a blocking monoclonal antibody that targeted the cell marker mesothelin appeared to prevent mesothelial cells from becoming apCAFs, as well as the formation of Tregs, the researchers suggested in a study published May 5 in the journal Cancer Cell.
By comparing the mice models with tumor tissues from 37 pancreatic cancer patients, the researchers were able to demonstrate that apCAFs also exist in humans. It means there’s potential for a similar antibody therapy to be effective in both species.
No truly effective treatments are currently available for pancreatic cancer, a disease that is diagnosed in around 56,000 Americans a year, the researchers pointed out. Only 10% of patients survive five years beyond their diagnosis.
The next step will be further research in animal models, but the researchers hope the findings will eventually lead to a treatment for humans that involves administering anti-mesothelin antibodies in combination with immunotherapies that stimulate the immune system to fight cancers.
Mesothelin is already a popular option being explored by cancer-focused pharmas, with Bayer among those with potential therapies in the clinic.
Further studies are still needed to fully determine how different populations of CAF cells interact as well as the relationship between CAFs and immune cells, the researchers added.
“By targeting antigen-presenting cancer-associated fibroblasts, we might someday be able significantly to enhance the activity of immune therapy in pancreatic cancer patients,” said Huang.
Given that most organs are lined by mesothelium, the researchers speculated that their findings could have benefits for cancers well beyond the pancreas.