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Senior Citizen Health & Medicine
Researchers Show Immune System Can Make Cancers
Become Dormant
'Cancer is typically a disease of the elderly
so
there probably was no evolutionary pressure for the immune system to
find a way to fight cancer'
Nov. 19, 2007 - A multinational team of researchers
has shown for the first time that the immune system can stop the growth
of a cancerous tumor without actually killing it. Scientists have worked
for years to use the immune system to eradicate cancers, a technique
known as immunotherapy, but this study may lead to a more workable
alternative that turns cancer into a controllable disease.
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The new findings prove an alternate to this
approach exists: When the cancer can't be killed with immune attacks, it
may be possible to find ways to use the immune system to contain it.
The results also may help explain why some tumors
seem to suddenly stop growing and go into a lasting period of dormancy.
The study appears today in the advance online publication of Nature.
"Thanks to the animal model we have developed,
scientists can now reproduce this condition of tumor dormancy in the
laboratory and look directly at cancer cells being held in check by the
immune system," says co-author Robert Schreiber, Ph.D., Alumni Professor
of Pathology and Immunology at Washington University School of Medicine
in St. Louis.
"That will allow us to see if we can model this
state therapeutically."
The study's authors call the cancer-immune system
stalemate "equilibrium." During equilibrium, the immune system both
decreases the cancer's drive to replicate and kills some of the
cancerous cells, but not quickly enough to eliminate or shrink the
tumor.
"We may one day be able to use immunotherapy to
artificially induce equilibrium and convert cancer into a chronic but
controllable disease," suggests co-author Mark J. Smyth, Ph.D.,
professor of the Cancer Immunology Program at the Peter McCallum Cancer
Centre in Melbourne, Australia.
Proper immune function is now appreciated as
another important factor in preventing the development of some cancers.
Further research and clinical validation of this process may also turn
established cancers into a chronic condition, similar to other serious
diseases that are controlled long-term by taking a medicine."
Scientists first proposed that the immune system
might be able to recognize cancer cells as potentially harmful more than
a century ago. Under a theory that came to be called cancer
immunosurveillance, researchers suggested that if this recognition took
place, the immune system would attack tumors with the same weapons it
uses to eliminate invading microorganisms.
Current immunotherapy efforts use therapeutic
agents to increase the chances that the immune system will recognize and
attack tumors.
But cancer immunosurveillance has been
controversial. The theory had begun to fall out of favor over the years,
and in 2001, Schreiber, graduate students Vijay Shankaran and Gavin
Dunn, and Lloyd Old, M.D., director of the New York branch of the Ludwig
Institute for Cancer Research, proposed a major revision. They called
their new model cancer immunoediting.
Like the older theory, cancer immunoediting
suggests that conflict between cancers and the immune system naturally
takes place but proposes that three very different outcomes can result.
The immune system can eliminate cancer, destroying it; the immune system
can establish equilibrium with cancer, checking its growth but not
eradicating 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 existence mainly on the basis of other doctors' clinical
experiences. Examples included cancers that inexplicably go into
remission for years. In addition, there have been hints that in a few
cases organ transplants have transferred undetected dormant tumors to
the recipients.
To directly observe dormant tumors in mice,
researchers injected them with small doses of a chemical carcinogen.
Mice that developed outright tumors were set aside; the remaining mice
had small, stable masses at the site of the injections. When certain
components of these animals' immune systems were disabled, the small
growths became full-blown cancers, suggesting that the immune system had
previously been 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, who have moved beyond their reproductive years, so there
probably was no evolutionary pressure for the immune system to find a
way to fight cancer."
Schreiber, Smyth and Old speculate that from the
immune system's point-of-view, a cancerous cell may look like a cell
infected by an invading microorganism. To overcome the safeguards that
prevent the immune system from attacking the body's own tissues, the
tumor has to have a high level of immunogenicity, or ability to provoke
an immune reaction.
Cancer cells can reduce their immunogenicity by
changing the materials they present to the immune system to more closely
resemble those presented by normal tissue. This enables the third
outcome of the immunoediting theory: escape.
Equilibrium sometimes may be a more common outcome
of tumor-immune encounters than elimination. According to the
researchers' theory, some of us may harbor dormant tumors that either
developed spontaneously or from exposure to carcinogens. They propose
that these quiescent tumors are unleashed only as we age or are exposed
to environmental, infectious or physical stresses that cause a breakdown
of the immune system.
To follow up, researchers plan a molecular-level
investigation of what happens in tumors and the immune system during
equilibrium. They also want to test their results' applicability both in
humans and in different types of cancers.
"For example, we need to look at which tissues are
regularly edited by the immune system and at how closely the immune
system watches over these tissues," Schreiber says. "If you completely
knock out the immune system in mice, you'll see tumors spring up in some
tissues but not in others, and this suggests that there may be differing
levels of immune system monitoring in different tissue types."
"Over the past decade, remarkable advances have
been made in our understanding of how the immune system reacts against
cancer and influences the course of the disease, and defining the
equilibrium phase of cancer immunoediting represents the newest
milestone in these advances," says Old.
"The challenge now is to incorporate these findings
into our thinking about human cancer and to develop immunotherapeutic
strategies that complement current methods of cancer treatment."
Editor's Notes:
Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ,
Old LJ, Smyth MJ, Schreiber RD. Adaptive immunity maintains occult
cancer in an equilibrium state. Nature, 2007. Advance online publication
(10.1038/Nature 06309)
Funding from the National Cancer Institute, the
Ludwig Institute for Cancer Research, the Cancer Research Institute, the
Atlantic Philanthropies, and the National Medical Research Council of
Australia supported this research.
Washington University School of Medicine's 2,100
employed and volunteer faculty physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine
is one of the leading medical research, teaching and patient care
institutions in the nation, currently ranked fourth in the nation by
U.S. News & World Report. Through its affiliations with Barnes-Jewish
and St. Louis Children's hospitals, the School of Medicine is linked to
BJC HealthCare.
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