Each year, approximately 700,000 patients undergo primary tumor resection, nearly half of whom will experience recurrence at some point, and many of these patients will eventually die from their disease. The conventional wisdom is that tumors recur because they acquire new genetic mutations that make them more aggressive and make drugs less likely to cross the cells and thus become resistant to antitumor therapy. However, researchers at the Perelman School of Medicine at the University of Pennsylvania have shown in animal models that the increased aggressiveness of recurrent tumors may be due to changes in the body’s immune system. The findings were published in a recent issue of Proceedings of the National Academy of Sciences (PNSA). Dr. Sunil Singhal, MD, senior author of the study and director of the Thoracic Surgery Research Laboratory at Perelman School of Medicine and assistant professor of surgery, said, “Typically, when a patient’s tumor recurs, oncologists give them the appropriate treatment, mostly like they would for a primary tumor, by using drugs that target the tumor cells themselves. But we found that attacking the tumor cells while knocking out the ‘bad’ immune cells that protect the tumor may work better.” To assess the effect of the anti-cancer vaccine on primary and recurrent tumors, the researchers immunized mice with the vaccine that had either primary or recurrent tumors in their lateral abdominal walls. Although both groups of animals developed an immune response to the vaccination, only the animals in the primary tumor group showed tumor shrinkage following a response to the vaccine. Animals in the recurrent tumor group responded to the vaccine but appeared to have no effect. Furthermore, this pattern of results was observed for several different vaccines. Although current popular models of tumor recurrence emphasize genetic alterations in the tumor cells themselves, Singhal and colleagues were not able to identify substantial genetic or behavioral differences in recurrent tumors relative to primary tumors that could explain the response pattern. Instead, when the team looked at the types of immune cells within and around the tumors, Singhal’s group found a big difference. There was a large increase in the number of regulatory T cells among the recurrent tumor mice compared to the primary tumor mice, Singhal said, adding that this may be critical because regulatory T cells are responsible for keeping other immune cells under control and blocking the immune response. In addition, macrophages, which protect tumor cells from immune system (attack), were also increased in number and activity in the recurrent tumor group of animals/mice. Notably, when the researchers treated the recurrent tumor animals with drugs that blocked macrophage activity, tumor growth was significantly slowed. Singhal said it is not clear what triggers the changes in the immune system, and his group has begun to look for the signaling molecules that do. In the meantime, however, he noted that there are newly approved and experimental drugs that can block regulatory T cells. Given his group’s new findings, he believes testing these drugs (in combination with drugs that can attack the tumor cells themselves) in patients with relapsing disease may also be an important advance for patients.