Researchers have shown in mice that the immune system can restrain the growth of cancer cells for extended periods, preventing dormant cancers from developing into life-threatening tumors. The findings raise the possibility that a new class of immune therapies could be developed to control rather than eliminate cancer cells.

Using the human immune system to keep dormant tumors in check may be a worthy goal of immune therapies, says Dr. Robert Schreiber of the Washington University School of Medicine, who co-led the study ¹ with Dr. Mark Smyth at the Peter MacCallum Cancer Centre in Victoria, Australia.

The immune system is often described as a double-edged sword for cancer because it appears to both prevent and promote the disease. For instance, acute inflammation may induce antitumor immunity that may eradicate cancer cells, while chronic inflammation may set the stage for cancer. The new results, published online in Nature last month, point to another role: maintaining tumors in a state of dormancy, or equilibrium.

"We hope that this work will open up a new appreciation of the many ways the immune system controls cancer," says Dr. Schreiber. The experiments were done in separate labs using different types of mice, but the results were the same. If they are generalizable to other tumors and extended to humans, the findings may help explain clinical observations about cancer, such as why the disease tends to occur late in life.

"It's possible that part of the reason the disease takes so long to develop is that tumors get held in an equilibrium state for a substantial period of time," notes Dr. Schreiber.

The findings lend support to recent studies ² showing that the presence or absence of certain immune cells in ovarian and colorectal tumors may predict the survival of patients with these diseases. The results may also shed light on why cancer cells are present in individuals who have no clinical signs of disease, such as some men with prostate cancer.

The findings could also help explain reports of melanoma skin cancer being transferred through organ transplantation. A letter to the New England Journal of Medicine in 2003 reported that two patients developed melanoma after each received a kidney from the same donor. The donor had been treated for melanoma 16 years earlier and was considered free of cancer, an investigation revealed. Evidently, the donor's melanoma had been under immune control for those years, but was awakened in the recipients, whose immune systems were suppressed to prevent organ rejection.

Dr. Schreiber and his colleagues are now studying the molecular basis of equilibrium. With the isolation of dormant tumors for the first time, researchers will be able to compare the genetic signatures of these lesions with those of lesions that became cancerous even in individuals with competent immune systems.

To isolate the dormant tumors, the researchers injected mice with low doses of methylcholanthrene, a carcinogen. A fifth of the mice developed fatal tumors. The surviving animals appeared healthy, but about half were found to have nodules near the injection sites that contained a mixture of tumors cells and immune cells. These were dormant tumors.

The tumors were held in a dormant state by the adaptive immune system, which involves immune cells such as T cells, the researchers found. When they blocked the critical immune cells, the tumors started to grow almost immediately.

"This study is the next step in our understanding of how the immune system interacts with cancer and influences the outcome of cancer," says co-author Dr. Lloyd Old of the Ludwig Institute for Cancer Research. "The challenge now is to understand the mechanisms that allow the immune system and the cancer to come to a state of dormancy, or equilibrium."

In theory, finding ways to augment a person's adaptive immune system could increase control over cancer. "We may be able to induce a chronic state of equilibrium that would render cancer into more of a controllable disease such as diabetes," Dr. Schreiber says. "If we currently cannot use the immune system to cure cancer, maybe we can use it to control the disease."

—Edward R. Winstead