|Tumors Use ‘Hijacking’ Trick to Evade Attack by Immune Cells
Researchers have identified a potential mechanism by which tumors in mice escape
attack from antitumor immune cells. This escape is facilitated when tumors produce
a molecule called adenosine that inactivates antitumor immune cells by binding
to receptors on their cell surfaces, the researchers found. Consequently, the
immune cells behave as though the tumors are normal tissue, and an attack is
averted. This research was conducted by scientists at the National Cancer Institute
(NCI) and the National Institute of Allergy and Infectious Diseases (NIAID),
both part of the National Institutes of Health (NIH), and their collaborators.
The results are reported in the August 9, 2006, issue of Proceedings of the
National Academy of Sciences.
“This work may be complementary to efforts of cancer immunologists who have
developed many clever ways to improve the development of antitumor T cells,” said
Elias A. Zerhouni, M.D., NIH Director. “The cross-fertilization of research between
the field of immunology and cancer is a fruitful one that is paying dividends
with this new finding.”
“Tumors have hijacked a mechanism that evolved to protect normal tissues from
collateral damage that occurs when the body mounts a defense against infection,” said
lead researcher Misha Sitkovsky, Ph.D., who until recently was at NIAID. Sitkovsky
is now at the New England Inflammation and Tissue Protection Institute, a consortium
at Northeastern University in Boston, Mass.
The findings extend research published in Nature in 2001 by Sitkovsky
and colleagues into the role of adenosine in regulating inflammation. Inflammatory
chemicals produced by the immune system in response to infection or injury must
eventually be switched off so that excessive tissue damage can be avoided.
Sitkovsky and his colleagues have shown that one consequence of inflammation — a
drop in oxygen levels in the inflamed tissues — triggers the release of
adenosine from surrounding cells and serves as a tissue-protecting stop signal.
This is because when adenosine binds to so-called A2A adenosine receptors on
immune cells in the inflamed region, the production of damaging inflammatory
molecules is slowed.
In the new study, the researchers tested whether the same mechanism protects
cancerous tissues from antitumor T cells by evaluating the effects of genetically
deleting A2A adenosine receptors in mice. The experiments showed that antitumor
T cells that lack A2A adenosine receptors can overcome tumor defenses and eradicate
“We showed that if antitumor T cells do not express A2A adenosine receptors
due to a genetic deletion, then these antitumor T cells can overcome adenosine-based
tumor defense mechanisms. As a result, the majority of these mice rejected their
tumors and survived significantly longer,” said co-researcher Scott Abrams, Ph.D.,
of NCI’s Center for Cancer Research. By comparison, normal mice that had antitumor
T cells with intact A2A adenosine receptors experienced uncontrolled tumor growth
and died. Abrams added, “These proof-of-concept experiments also raise the idea
that this type of tumor escape mechanism may serve as a target for therapeutic
To begin to explore that idea, the researchers pharmacologically inactivated
the A2A adenosine receptor using substances such as caffeine and others to make
antitumor T cells less susceptible to inhibition by tumor-produced adenosine.
The majority of mice in these experiments had much better antitumor immune responses
and delayed tumor growth.
The genetic inactivation strategy was not effective in about 40 percent of the
mice, however. The researchers suggest that one reason may be the existence of
other adenosine receptors in these mice, and identifying these molecules will
be a focus of future research.
“Now we may be able to prevent a hostile tumor microenvironment from inhibiting
the antitumor T cells. I have been extremely fascinated and puzzled by the paradoxical
coexistence of tumors and anti-tumor immune cells in the same cancer patient,” added
Sitkovsky. “I have been considering this contradiction for the past 30 years.”
“Greater understanding of the tumor microenvironment and its relationship to
other cells in the body is not just enhancing our knowledge of cancer; it could
eventually lead to new treatments and better ways to monitor those treatments,” said
NCI Acting Director John E. Niederhuber, M.D.
For more information about cancer, please visit the NCI Web site at http://www.cancer.gov,
or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
NIAID supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted infections,
influenza, tuberculosis, malaria and illness from potential agents of bioterrorism.
NIAID also supports research on basic immunology, transplantation and immune-related
disorders, including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.