Blocking inflammation after radiation therapy led to improved survival in mouse model.
Pancreatic cancer has long been one of the hardest to treat. Now, in a new study, researchers at the Perelman School of Medicine at the University of Pennsylvania have illuminated one of this cancer’s major resistance mechanisms: a form of inflammation that is triggered by the tumor in response to treatment and helps keep tumor cells alive.

Blocking this inflammation after radiation therapy brought a significant improvement in survival in a mouse model of the disease.

The study was published in the January issue of the journal Clinical Cancer Research.

Studies in recent years by Beatty’s laboratory and others have pointed to one potential source of this treatment resistance: Pancreatic tumors tend to surround themselves with a protective “microenvironment.”

This tumor–protecting microenvironment includes inflammatory white blood cells called monocytes and macrophages. In pancreatic cancer, their activity boosts tumor growth and spread, and may also help suppress T cells and other immune elements that would otherwise attack the tumor.

An early–stage clinical study by another institution, published in the Lancet Oncology journal in May 2016, combined chemotherapy with an experimental drug that blocks CCR2, a receptor on monocytes and macrophages whose activation stimulates these cells to infiltrate tumors. Though the study was small, the results were promising: blocking CCR2 led to a much better tumor response compared to chemo alone.

For their new study, Beatty and colleagues tested a similar inflammation–blocking strategy, this time in combination with radiation therapy. Radiation is often used to treat pancreatic tumors that haven’t spread but can’t be removed with surgery.

The first author of the study is Anusha Kalbasi MD, clinical instructor at University of California, Los Angeles School of Medicine. In mice with pancreatic tumors, Kalbasi and other members of the team found relatively high levels of inflammatory compounds including CCL2, the signaling molecule that activates CCR2 on monocytes and macrophages to make these cells migrate to tumors. After a large dose of radiation therapy, comparable to what human patients receive, CCL2 levels rose even higher – in fact, several times higher – and the scientists found that it was being secreted by the tumor cells themselves.

“They’re dying in response to the radiation, and that’s causing them to release these chemical signals that call in help, which then allows them to regrow,” Beatty said. The tumors’ recruitment of these inflammatory cells thus enabled them to resist what would otherwise have been a deadly dose of radiation, so that their growth slowed only modestly compared to control mice that had received no radiation. By contrast, when the team treated the mice with radiation plus a CCL2–blocking antibody, the tumors’ recruitment of monocytes and macrophages was sharply reduced, and the tumor growth was slowed more dramatically. “Not only did the combination of radiation and CCL2–blockade slow tumor growth, it prolonged survival in mice as well,” said Kalbasi. The boost in survival time allowed the mice to live roughly 25 percent longer than those treated with radiation alone.

To the Penn scientists, the findings indicate that blocking the CCL2–CCR2 inflammatory pathway in pancreatic cancer is worth investigating as an add–on to radiation therapy, not just to chemotherapy. Along those lines, the researchers now plan to investigate the relationship between tumor–associated inflammatory cells and the response to radiation therapy in human pancreatic cancer patients.