One challenge in treating pancreatic cancer is getting chemotherapy to reach the tumor cells. That’s because the tumors are surrounded by a forbidding microenvironment, a barrier of cells that both promote the tumor and block treatment. Researchers have known the barrier is coordinated by cells from the body’s own innate immune system—macrophages that have been alternatively activated. But until now, researchers have known little about how the body’s inflammatory macrophages, which typically serve to get rid of harmful, foreign matter, go rogue and turn into tumor-enhancing cells.
A new study from the lab of cancer biologist Peter Storz, Ph.D., described a mechanism that spurs the initiation of dangerous macrophages and makes them capable of promoting a tumor. Published in Cell Reports, the study showed the signaling molecule interleukin-13 (or IL-13), which is released by the cells of pre-cancerous pancreatic lesions, prompts inflammatory macrophages to alter their normal behavior. Once stimulated, the macrophages begin releasing factors that drive the growth of pancreatic tumors and wall them off from treatment. But the team found the process could be interrupted, too. “When we gave mice an antibody that neutralized the IL-13, we were able to decrease the presence of the alternately-activated macrophages, and decrease the growth of tumorigenic lesions,” says Dr. Storz, of the Mayo campus in Florida. Significantly, he adds, understanding the initiation of tumor-promoting macrophages may be broadly useful: the same stimulated macrophages are known to turn up around other tumors, including those of breast and lung cancer.
While the finding is the first to explain the mystery of this tumor-enhancing mechanism in pancreatic cancer, it also points the way to potential treatments. “Now that we know the steps by which the precancerous cells speak to the macrophage population and the macrophages speak to the tumors, we now have several points of possible intervention,” says Dr. Storz. He is currently developing a clinical trial to test one new approach to treating pancreatic cancer, adding an IL-13 antibody to standard-of-care chemotherapy. “Our hope is that the antibody will neutralize the IL-13 in patients, making pancreatic tumors more susceptible to treatment,” he says.
Dr. Storz’ research is funded by grants from the National Institutes of Health and the Chartrand Foundation.
– Kate Ledger, May 10, 2017