Pancreatic cancer is a ruthless killer. Often diagnosed after it has already metastasized, it is also notoriously difficult to treat with standard chemotherapy and radiation. Even immunotherapies have so far been ineffective at significantly improving pancreatic cancer survival rates, which remain the worst of all cancer types.
Now, new research by CRI postdoctoral researcher Ingunn Stromnes, Ph.D., suggests why: pancreatic tumors wrap themselves in a defense cloak that protects them from an immune attack.
Scientists have known for several years that certain “regulatory” cells of the immune system keep immune responses in check. This is an important safeguard against auto-immunity—when the immune system attacks the body’s own cells. But scientists are now learning that cancer cells also make use of such regulatory cells, sometimes strategically luring them to the site of a tumor as a form of defense.
Stomnes, a postdoctoral researcher working with Philip Greenberg, M.D., and Sunil Hingorani, M.D., Ph.D., at the Fred Hutchinson Cancer Center at the University of Washington, has developed a mouse model of pancreatic ductal adenocarcinoma that is particularly good for studying this disease. Using her mouse model, Stromnes watched as pancreatic tumors developed and noticed that one type of regulatory immune cell stood out. Called granulocyte-myeloid-derived suppressor cells (Gr-MDSCs), these cells increased in number at precisely the same time that pancreatic tumors became more aggressively invasive. Suspecting that the two events were related, Stromnes looked and discovered that the tumors were indeed attracting these Gr-MDSCs by releasing a protein called granulocyte macrophage colony-stimulating factor (GM-CSF).
At the site of the tumor, the Gr-MDSCs formed a defensive barrier, preventing the immune system’s “killer” T cell from reaching the tumor. Not only that, but the Gr-MDSCs also actually prevented T cells from dividing and even caused their death.
What would happen if these Gr-MDSCs could be removed? To answer this question, Stromnes administered a monoclonal antibody targeted against a particular antigen found on Gr-MDSCs, selectively depleting these cells from the tumor. Once this barrier was removed, she found that the killer T cells were able to enter the tumors and launch an assault.
On the left, Gr-MDSCs (green) prevent killer T cells (red) from entering the tumor; on the right, depleting the Gr-MDSCs allows the killer T cells to mount an attack. Credit: Hingorani Lab, Fred Hutchinson Cancer Research Center
“The findings are important because they show that the tumor microenvironment itself, and in particular a specific subset of cells in the tumor, is preventing T cells from trafficking to the tumor and mounting a response,” Stromnes said.
There are also important treatment consequences. Unless cancer immunologists can find a way to penetrate this armor surrounding the tumor, then immunotherapies such as adoptive T cell therapy are likely to be ineffective at treating pancreatic cancer.
That’s where Stromnes’s technique could prove valuable. “We’re trying to get the helpful immune cells into the tumors, and our results show that to do that, we need to get rid of these inhibitory cells the tumors have co-opted,” Stromnes said.
Ultimately, the team hopes to combine their armor penetrating-approach with adoptive T cell therapy, as well as standard chemo.
“Our goal is not incremental advances,” co-author Hingorani said. “We want to put as big a hurt on pancreas cancer as possible.”
Citation: Stromnes, I. M. et al., Gut Published Online First: Feb. 20, 2014.