PHILADELPHIA — A study published this week in Cancer Cell from the Perelman School of Medicine and the Abramson Cancer Center at the University of Pennsylvania describes how pancreatic cancer cells produce a protein that attracts immune cells and tricks them into helping cancer cells grow. Blocking the protein may be also prove to be a new way to treat pancreatic cancer.
Pancreatic cancer is one of the most deadly types of cancer, mostly due to its aggressiveness and its ability to suppress the cancer-fighting properties of the immune system. Most pancreatic cancer cells contain a mutation in the KRAS gene. The Penn team looked to see how mutated KRAS proteins give pancreatic cancer its distinguishing properties. A group from New York University School of Medicine led by Dafna Bar-Sagi took a complementary approach and reported its findings in another manuscript also published this week in Cancer Cell.
"Both our group and the group from NYU have discovered a critical way in which pancreatic tumor cells cripple the immune system. From very early on, tumor cells produce a molecule that drives inflammatory cells to cloak the tumor and prevent other immune cells from killing the cancer," says Penn's senior author Robert Vonderheide, MD, DPhil, associate professor of Medicine and associate investigator in the Abramson Family Cancer Research Institute. "We found that simply disabling the ability of tumors to make this molecule leads to a house-of-cards effect that resulted in massive tumor death in experimental models."
Most notorious about tumors of the pancreas is the dense network surrounding the tumor that suppresses the immune system from killing the cancer. "We have long wondered: Why would pancreatic cancer cells go to such great lengths to suppress the immune system if the immune system did not hold the power to kill the cancer cells? Our findings demonstrate that if these suppression mechanisms are disabled, pancreatic cancer cells can be killed by the immune system," says Vonderheide.
Using mouse models of pancreatic cancer, the two teams each found that mutated KRAS triggers pancreatic tumors to express a protein called GM-CSF. They also discovered that tumor GM-CSF proteins recruit immature immune cells to the areas surrounding the tumor and then coax those cells to mature into myeloid-derived suppressor cells. These new cells suppress the surveillance function of other immune cells that normally seek out and destroy tumor cells.
In this way, pancreatic cells escape being seen by the body's immune system and are free to grow and divide. However, blocking GM-CSF inhibited myeloid-derived suppressor cells and enabled the immune system to fight tumor development.
"Our findings suggest new possibilities for treating patients with pancreatic cancer. Rather than going after the tumor cell directly, we hypothesize that new drugs that neutralize the immune suppressive features of the tumor may be able to unleash the immune system to benefit patients," explains Vonderheide. "We obviously have a great deal more work to do in this regard, but we are excited by the prospect. In particular, we look forward to testing our idea in future clinical trials."
This research was supported by the Abramson Family Cancer Research Institute and by grants from the Cancer Research Institute; the National Cancer Institute of the National Institutes of Health (K12 CA076931 and K08 088945); Gabrielle's Angel Foundation for Cancer Research; the American Gastroenterological Association; and the Pennsylvania Department of Health.
Co-authors in addition to Vonderheide are first author Lauren J Bayne; Gregory L Beatty, MD, PhD; Nirag Jhala, MD; Carolyn E Clark, PhD; Andrew D Rhim, MD; and Ben Z. Stanger, MD, PhD, all from Penn.