Immune System Helps Prevent Tumors After All

Their paper appears in the April 26 issue of the journal Nature. "This sheds light on an age-old controversy and suggests new possibilities for cancer therapy," says Robert D. Schreiber, Ph.D., the Alumni Professor of Pathology and Immunology and professor of molecular microbiology at Washington University School of Medicine in St. Louis.

Schreiber led the study. Vijay Shankaran, an M.D./Ph.D. student in Schreiber’s lab, was first author of the paper. The St. Louis researchers collaborated with Lloyd J. Old, M.D., director and CEO of the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center in New York.

Because the immune system protects the body against infection, scientists once predicted that it also protects against tumor cells. But several studies in the 1970s found that "nude" mice — mice thought to lack lymphocytes — did not develop more chemically-induced or spontaneous tumors than normal mice. So the immune system theory was abandoned.

However, subsequent studies revealed that these nude mice were not completely free of lymphocytes and therefore did not represent a model of tumor formation in the context of an impaired immune system. Recently, Schreiber and others have found evidence that both lymphocytes and gamma interferon (IFNg), a protein produced by certain lymphocytes, might play important roles in tumor prevention. So Schreiber and colleagues decided to explore further.

In this current paper, they used a strain of mice that completely lacked functional lymphocytes. This was accomplished by inactivating a lymphocyte-specific gene called RAG2. When these mice were injected with the chemical carcinogen MCA, 58 percent of them developed tumors. In previous studies, the group obtained a similar result when they injected MCA into mice that lacked either the receptor for IFNg or one of the proteins required for the receptor to function, Stat1. In contrast, only 19 percent of the normal mice developed tumors after MCA exposure.

When mice generated with two disrupted genes — the gene for RAG2 and the gene for Stat1 — were injected with MCA, 72 percent of them developed tumors. Statistically, this was not greater than the incidence of tumors in mice that lacked just one gene or the other. Therefore, the researchers concluded that RAG2 and the IFNg receptor have overlapping roles.

"We think the two are potentially part of the same mechanism but represent different steps in the process," explains Schreiber. "IFNg makes tumor cells expose themselves to the immune system. After seeing the abnormal proteins in the tumor, the lymphocytes eliminate the tumor cells."

The team also determined whether the three groups of mice — normal, RAG2-deficient, and deficient in both RAG2 and Stat1 — developed tumors spontaneously, without being exposed to the carcinogen. By 15 months, two of 11 normal mice had noncancerous tumors and the rest were tumor-free. In contrast, all 12 RAG2-deficient mice had developed tumors, half of which were cancerous.

Surprisingly, all 11 mice lacking both RAG2 and Stat1 developed cancerous tumors. Six expressed cancerous breast tumors well before 15 months. This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNg receptor. The other five developed cancers of the intestinal tract and lung. The researchers concluded that, while the roles of lymphocytes and IFNg overlap, IFNg also might prevent tumor formation via mechanisms not involving the immune system.

"These results show that both IFNg and lymphocytes are involved in the prevention of tumors and that the two interact with one another to protect individuals from cancer development," says Schreiber. "That’s the good news."

There’s also bad news, however. When MCA-induced tumors from normal mice were transplanted into healthy normal mice, they continued growing. But eight of 20 tumors from RAG2-deficient mice transplanted into healthy mice were rejected. Apparently, the immune system in these healthy mice was better equipped to recognize — and reject — tumor cells from RAG2-deficient mice than tumor cells that had developed in mice with intact lymphocytes.

"As a result of protecting the body, the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system," Schreiber says.

When a role for the immune system in tumor formation was proposed decades ago, scientists envisioned a process called immunosurveillance, wherein the immune system catches a cell at the beginning of its transformation into a tumor cell. In contrast, Schreiber and his colleagues think their discoveries suggest immunoediting, in which the immune system constantly eliminates certain types of tumor cells and also changes the characteristics of others.

"Immunoediting could explain why the immune system can select for tumors that are more capable of escaping the immune system as they continue to develop," says Schreiber. "If this process is always occurring, it can have multiple outcomes, one of which is protection. But if you’re unlucky, transformed tumor cells might alter themselves so the immune system can pick out only a few. The others continue growing."

The researchers examined one potential way to flag tumors for easier identification by the immune system. They added a protein called TAP1. This molecule appears to be absent from some tumors that escape immune detection.

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy normal mice, they grew in an extremely rapid manner. However, if these tumors first were tagged with TAP1 before being transplanted into healthy mice, they were rejected. In contrast, the tagged tumors were not rejected when transplanted into RAG2-deficient mice. Thus, tagging the tumors facilitated their detection and elimination by the immune system.

"We showed that if a tumor is forced to reveal itself to the immune system, it often is rejected," Schreiber explains. "We think that tagged tumor could be used to train the immune system to reject others like it. This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process."

Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNg and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature, April 26, 2001.

Funding from the National Institutes of Health and the Cancer Research Institute supported this research.