Pancreatic cancer cells able to recruit bodyguards
The image at left shows a large number of immunosuppressive cells, in green, in a pancreatic cancer tumor. In the image at right, most of the immune system-suppressing cells have been removed, allowing T cells, in red, to attack the cancer. HINGORANI LAB/FRED HUTCH
Suncoast News staff
Published: March 5, 2014
Updated: March 5, 2014 at 04:08 PM
Why are pancreatic cancer cells, one of the most ruthless killers, so hard to beat? For one thing, they’re not in the battle alone, according to newly published research. Based on experiments with a mouse model of human pancreatic cancer, investigators at the Fred Hutchinson Cancer Research Center, in Seattle, say malignant pancreas cells are able to surround themselves with specialized cells that keep the body’s immune system from mounting an attack against them. Take away these suppressor cells, the Fred Hutch scientists say, and the disease-fighting white blood cells known as T cells can begin taking out the pancreatic cancer cells. Based on their findings, published Feb. 20 in the journal Gut, the researchers are planning to develop a treatment for pancreatic cancer that will combine immunotherapy and chemotherapy and strike a major blow against the disease.
“Our goal is not incremental advances,” said study leader Sunil Hingorani, an associate member of the Clinical Research Division at Fred Hutch. “We want to put as big a hurt on pancreatic cancer as possible.” That would be welcome news for doctors because about 45,000 cases of pancreatic cancer are diagnosed each year in the United States and almost invariably prove fatal. As Hingorani puts it, pancreatic cancer is so resistant to treatment because it “doesn’t obey the rules.” Its malignant cells waste little time before beginning to spread and don’t need much of a blood supply to survive. In fact, pancreatic tumors restrict blood flow by manufacturing a fibrous wall that blocks blood vessels trying to enter the malignant mass. This greatly reduced blood flow makes it difficult to get cancer-killing drugs into pancreatic tumors. This problem prompted Hingorani and his colleagues to develop the mouse model of pancreatic cancer. They used it to discover an enzyme that makes it easier to get chemotherapy drugs into the tumors. They then decided to use the same model to explore why the immune system has such a tough time against pancreatic cancer. After finding several types of immunosuppressive cells in pancreatic tumors, Hingorani, in collaboration with Fred Hutch Clinical Research Division immunologist Philip Greenberg and Ingunn Stromnes, a postdoctoral researcher who is mentored by Hingorani and Greenberg, began looking for ways to combat them. During research she led, Stromnes discovered that one type of suppressor cell was playing the dominant role. Once pancreatic cancer starts to spread, the number of these bone-marrow-derived cells, called granulocyte-myeloid-derived suppressor cells, or Gr-MDSCs, began showing up in large numbers. Further experiments showed the tumors were producing a protein known as granulocyte macrophage colony-stimulating factor. It is the GM-CSF that attracts the Gr-MDSCs. The suppressor cells block attacks on the tumor by keeping the T cells from reproducing themselves and even causing them to die. When the supply of Gr-MDSCs in the tumor is reduced, the T cells go on the attack and do the sort of damage to the cancer cells they are supposed to do, Stromnes found. This damage appears to have a helpful side effect, reducing the pressure on the tumor blood vessels, potentially making it easier to get cancer-killing drugs into the tumor. The researchers are now working on a T cell-based therapy for pancreatic cancer. Their study published in Gut was supported by the National Cancer Institute, the Giles W. and Elise G. Mead Foundation, the Safeway Foundation, the Irvington Institute Fellowship Program of the Cancer Research Institute, the Jack & Sylvia Paul Fund to Support Collaborative Immunotherapy Research and the Fred Hutchinson/University of Washington Cancer Consortium.