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Immune system can drive cancers into dormant state

A multinational team of researchers has shown for thefirst time that the immune system can stop the growth of a canceroustumor without actually killing it. Scientists have been working for years to use the immune system to eradicate cancers, a technique known as immunotherapy. The newfindings prove an alternate to this approach exists: When the cancercan't be killed with immune attacks, it may be possible to find waysto use the immune system to contain it. The results also may helpexplain why some tumors seem to suddenly stop growing and go into alasting period of dormancy. The study appears Nov. 18, 2007 in the advance online publication of Nature. "Thanks to the animal model we have developed, scientists can nowreproduce this condition of tumor dormancy in the laboratory and lookdirectly at cancer cells being held in check by the immune system,"says co-author and Siteman Cancer Center member Robert Schreiber,PhD, Alumni Professor of Pathology and Immunology at WashingtonUniversity School of Medicine. "That will allow us to see if we canmodel this state therapeutically." The study's authors call the cancer-immune system stalemateequilibrium. During equilibrium, the immune system both decreases thecancer's drive to replicate and kills some of the cancerous cells butnot quickly enough to eliminate or shrink the tumor. "We may one day be able to use immunotherapy to artificially induceequilibrium and convert cancer into a chronic but controllabledisease," suggests co-author Mark Smyth, PhD, professor in the cancerimmunology program at the Peter McCallum Cancer Center in Melbourne,Australia. "Proper immune function is now appreciated as anotherimportant factor in preventing the development of some cancers.Further research and clinical validation of this process may alsoturn established cancers into a chronic condition, similar to otherserious diseases that are controlled long-term by taking a medicine." Scientists first proposed that the immune system might be able torecognize cancer cells as potentially harmful more than a centuryago. Under a theory that came to be called cancer immunosurveillance,researchers suggested that if this recognition took place, the immunesystem would attack tumors with the same weapons it uses to eliminateinvading microorganisms. Current immunotherapy efforts usetherapeutic agents to increase the chances that the immune systemwill recognize and attack tumors. But cancer immunosurveillance has been controversial. The theory hadbegun to fall out of favor over the years, and in 2001, Schreiber,graduate students Vijay Shankaran and Gavin Dunn, and Lloyd Old, MD,director of the New York branch of the Ludwig Institute for CancerResearch, proposed a major revision. They called their new modelcancer immunoediting. Like the older theory, cancer immunoediting suggests that conflictbetween cancers and the immune system naturally takes place butproposes that three very different outcomes can result. The immunesystem can eliminate cancer, destroying it; the immune system canestablish equilibrium with cancer, checking its growth but noteradicating it; or the cancer can escape from the immune system,likely becoming more malignant in the process. Until this latest study, evidence for the second outcome was lacking.Schreiber, Smyth and their colleagues posited equilibrium's existencemainly on the basis of other doctors' clinical experiences. Examplesincluded cancers that inexplicably go into remission for years. Inaddition, there have been hints that in a few cases, organtransplants have transferred undetected dormant tumors to recipients. To directly observe dormant tumors in mice, researchers injected themwith small doses of a chemical carcinogen. Mice that developedoutright tumors were set aside; the remaining mice had small, stablemasses at the site of the injections. When certain components ofthese animals' immune systems were disabled, the small growths becamefull-blown cancers, suggesting that the immune system had previouslybeen holding the tumors in check. "We don't think the immune system has evolved to handle cancers,"Schreiber notes. "Cancer is typically a disease of the elderly, whohave moved beyond their reproductive years, so there probably was noevolutionary pressure for the immune system to find a way to fightcancer." Schreiber, Smyth and Old speculate that from the immune system'spoint of view, a cancerous cell may look like a cell infected by aninvading microorganism. To overcome the safeguards that prevent theimmune system from attacking the body's own tissues, the tumor has tohave a high level of immunogenicity, or ability to provoke an immunereaction. Cancer cells can reduce their immunogenicity by changingthe materials they present to the immune system to more closelyresemble those presented by normal tissue. This enables the thirdoutcome of the immunoediting theory: escape. Equilibrium sometimes may be a more common outcome of tumor-immuneencounters than elimination. According to the researchers' theory,some of us may harbor dormant tumors that either developedspontaneously or from exposure to carcinogens. They propose thatthese quiescent tumors are unleashed only as we age or are exposed toenvironmental, infectious or physical stresses that cause a breakdownof the immune system. To follow up, researchers plan a molecular-level investigation ofwhat happens in tumors and the immune system during equilibrium. Theyalso want to test their results' applicability both in humans and indifferent types of cancers. "For example, we need to look at which tissues are regularly editedby the immune system and at how closely the immune system watchesover these tissues," Schreiber says. "If you completely knock out theimmune system in mice, you'll see tumors spring up in some tissuesbut not in others, and this suggests that there may be differinglevels of immune system monitoring in different tissue types." "Over the past decade, remarkable advances have been made in ourunderstanding of how the immune system reacts against cancer andinfluences the course of the disease, and defining the equilibriumphase of cancer immunoediting represents the newest milestone inthese advances," says Old. "The challenge now is to incorporate thesefindings into our thinking about human cancer and to developimmunotherapeutic strategies that complement current methods ofcancer treatment." Contact: Michael Purdy; 314-286-0122; purdym@wustl.edu