April 4, 2011

Breaking Down Pancreatic Tumor Defenses

Microscope image of several small round cells on a larger, spiky cell. Macrophages (the small round cells) attacking a cancer cell. Dr. Raowf Guirguis, NCI.

A new approach for attacking pancreatic tumors may lead to improved therapy for patients with inoperable disease, scientists report. The strategy offers hope for more effective techniques to eliminate tumors.

Pancreatic cancer is one of the most deadly types of cancer, especially in the later stages. More than 40,000 new cases are diagnosed nationwide every year. Most diagnoses are made once the cancer has already spread, making successful treatment nearly impossible. A major challenge in treating pancreatic tumors is overcoming their ability to force immune cells to tolerate and even support their growth.

A team of researchers at the University of Pennsylvania led by Dr. Gregory Beatty, Dr. Peter O'Dwyer and Dr. Robert Vonderheide tried a new approach to break down the tumors' defenses. They predicted that the immune system's T cells could be turned on by using an antibody to a cell-surface molecule called CD40, which controls the cells' activation. Having overcome the tumors' suppression, the T cells would then attack and kill the tumors. While the treatment proved effective in some patients, the reason was a surprise. The study was partially funded by NIH's National Cancer Institute (NCI) and appeared in the March 25, 2011, issue of Science.

The team first tested a combination treatment in pancreatic cancer patients who couldn’t be cured by surgery. The scientists administered a standard drug, gemcitabine, along with the CD40 antibody. The results were promising. CT scans showed that tumors shrank in 4 out of 21 patients, and average patient survival was longer than usually seen with gemcitabine alone. The team examined samples from the tumors after treatment, expecting to see T cells. Surprisingly, they didn't; rather, another type of immune cell, the macrophage, dominated the tumors. Macrophages are known to be activated by binding CD40 on other immune cells, but they weren't thought to be involved in fighting tumors.

To further investigate, the team used a genetically engineered mouse strain that develops pancreatic cancer spontaneously. After treatment with gemcitabine and CD40 antibody, the tumors shrank in 30% of the animals. As in the humans, the T cells weren't necessary for the shrinkage, and gemcitabine alone couldn't cause it.

When the researchers depleted macrophages from the mice, the tumors didn’t shrink with CD40 antibody treatment. Moreover, when the scientists cultured tumor cells with macrophages from the pancreas of treated animals, the macrophages proved to be effective cell killers. This suggested that the antibody treatment had overcome the tumor’s ability to suppress the macrophages. The team observed that the treatment caused the thick network of connective tissue around the tumors, called the stroma, to disintegrate. When they depleted macrophages again, the stroma stayed intact.

"Until this research, we thought the immune system needed to attack the cancer directly in order to be effective," explains Vonderheide. "Now we know that isn’t necessarily so. Attacking the dense tissues surrounding the cancer is another approach, similar to attacking a brick wall by dissolving the mortar in the wall. Ultimately, the immune system was able to eat away at this tissue surrounding the cancer, and the tumors fell apart as a result of that assault."

— by Allison Bierly, Ph.D.

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