Promising new approach for harnessing the immune
system to fight cancer released today
St. Jude researchers get immune system to shrink
melanoma cancer in mice without autoimmune reaction
Aug. 4, 2013 – Researchers announced today the
discovery of a way to target the immune system to shrink or eliminate
tumors in mice without causing dangerous autoimmune problems that are
often associated with current cancer treatments. They say it was
particularly dramatic in a mouse model of human melanoma cancer and
shows evidence it may operate in humans.
The report by scientists at St. Jude Children’s
Research Hospital published their study in the advance online edition of
The findings provide a new target for ongoing
efforts to develop immunotherapies to harness the immune system to fight
cancer and other diseases.
The work focused on white blood cells called
regulatory T cells. These specialized cells serve as the immune system’s
police force, working to control inflammation and guard against
autoimmune and inflammatory disease. Regulatory T cells can, however,
interfere with the immune system’s ability to fight cancer.
In this study, investigators identified a mechanism
that boosts the ability of regulatory T cells to cause problems by
blocking an effective anti-tumor immune response. The same process,
however, plays no role in maintaining immune balance or preventing the
misguided immune attack on healthy tissue that leads to autoimmune
problems, researchers reported.
Blocking this mechanism led to the elimination or
dramatic reduction of melanoma by the immune system in mice.
“Regulatory T cells are a major barrier to
effective anti-tumor immunity,” said the study’s corresponding author,
Dario Vignali, Ph.D., vice chair of the St. Jude Department of
“We have identified a mechanism that enhances the
ability of regulatory T cells to put the brakes on the immune response
in tumors but plays no role in immune system maintenance. For the first
time, we may now have an opportunity to selectively target the activity
of regulatory T cells for treatment of cancer without inducing
autoimmune or inflammatory complications.”
The mechanism is built around two proteins. One,
semaphorin-4a (Sema4a), is carried on the surface of various immune
cells that can spark inflammation. The other, neuropilin-1 (Nrp1), is
carried on the surface of regulatory T cells.
Vignali and his colleagues used a variety of
molecular and cellular techniques to show that Sema4a binding to Nrp1
turns on a biochemical pathway in mouse regulatory T cells that enhances
their function, stability and survival. When scientists eliminated Nrp1
on just regulatory T cells, those cells were unable to respond to
signals that normally bolstered their anti-inflammatory activity.
When investigators analyzed human regulatory T
cells, they found evidence that the pathway may also serve the same
In addition, more than 16 months after losing Nrp1
activity in their regulatory T cells, the mice showed no signs of
autoimmune or inflammatory complications. “That is significant because
mice and humans that lack or have substantial defects in regulatory T
cells develop lethal autoimmune disease,” Vignali said.
Knocking out or blocking the activity of Nrp1 on
regulatory T cells in mouse models of several human cancers, including
the deadly skin cancer melanoma, led to reduced, delayed or complete
elimination of the tumors. Blocking Sema4a had a similar anti-tumor
effect, researchers reported.
“The impact was particularly dramatic in a mouse
model of human melanoma,” Vignali said. “Mice lacking Nrp1 on regulatory
T cells were almost completely resistant to developing melanoma, but did
not develop any autoimmune or inflammatory complications.”
Although investigators have not yet identified
which cells carry Sema4a in tumors and boost regulatory T cell function,
the scientists did report that immune cells called plasmacytoid
dendritic cells (pDCs) provided more than half of the Sema4a in tumors
in this study. That was surprising because pDCs make up a very small
percentage of immune cells, and there is a long history of suppressive
interactions between regulatory T cells and pDCs in tumors, Vignali
said. Both cell types are recognized as inducing the immune system to
tolerate, rather than attack, tumors.
Researchers also provided new details of how the
Nrp1 pathway functions, including evidence that along with bolstering
the ability of regulatory T cells to suppress the immune response, the
pathway also helps maintain a stable population of regulatory T cells.
“This pathway does not just boost regulatory function. It may define how
regulatory T cells maintain their identity,” said Greg Delgoffe, Ph.D.,
a postdoctoral fellow in Vignali’s laboratory. Delgoffe and Seng-Ryong
Woo, Ph.D., a former postdoctoral fellow in Vignali’s laboratory, are
The other authors are Meghan Turnis, Cliff Guy,
Abigail Overacre, Matthew Bettini, Peter Vogel, David Finkelstein and
Creg Workman, all of St. Jude; David Gravano, formerly of St. Jude; and
Jody Bonnevier, R&D Systems, Inc., Minneapolis.
The study was funded in part by grants (AI091977,
AI039480 and AI098383) from the National Institutes of Health; a grant
(CA21765) from the National Cancer Center at NIH; and ALSAC.
Links to More Archived
Stories on Melanoma Cancer
a form of cancer that begins in melanocytes (cells that make the
pigment melanin). It may begin in a mole (skin melanoma), but
can also begin in other pigmented tissues, such as in the eye or
in the intestines.
men and women (44,250 men and 32,000 women) were expected to be
diagnosed with and 9,180 men and women to die of
melanoma of the skin
the median age at diagnosis for melanoma of the skin was 61
years of age.
0.6% were diagnosed under age 20; 6.8% between 20 and 34; 10.7%
between 35 and 44; 18.2% between 45 and 54; 21.6% between 55 and
64; 18.8% between 65 and 74; 16.7% between 75 and 84; and 6.6%
85+ years of age.
age-adjusted incidence rate was 21.0 per 100,000 men and women
the median age at death for melanoma of the skin was 68 years of
age. Approximately 0.1% died under age 20; 2.6% between 20 and
34; 5.6% between 35 and 44; 13.5% between 45 and 54; 19.9%
between 55 and 64; 21.2% between 65 and 74; 24.1% between 75 and
84; and 12.9% 85+ years of age.
age-adjusted death rate was 2.7 per 100,000 men and women per
year. These rates are based on patients who died in 2005-2009 in
Based on rates
from 2007-2009, 1.99% of men and women born today will be
diagnosed with melanoma of the skin at some time during their
lifetime. This number can also be expressed as 1 in 50 men and
women will be diagnosed with melanoma of the skin during their
lifetime. These statistics are called the
lifetime risk of
Sometimes it is
more useful to look at the
probability of developing
melanoma of the skin between two age groups. For example, 0.99%
of men will develop melanoma of the skin between their 50th and
70th birthdays compared to 0.60% for women
On January 1,
2009, in the United States there were approximately 876,344 men
and women alive who had a history of melanoma of the skin -
427,810 men and 448,534 women.