Scientists at Johns Hopkins and elsewhere say they
have mapped out an escape route that
cancers use to evade the body's immune system, allowing the
disease to spread unchecked.
In a report published in the July 1 issue of the
journal Nature Medicine, the Johns Hopkins
team, along with researchers from Florida and Nebraska,
describe how myeloid-derived suppressor
cells, which normally keep the immune system in check and
prevent it from attacking otherwise
healthy tissue, can suppress the anti-tumor response to
cancer.
These suppressor cells block other immune system
cells, CD8 "killer" T cells, from binding with
proteins that identify the foreign antigens on the surface
of unhealthy cancer cells, marking them for
destruction, the team reports.
The good news, the scientists say, is that their
experiments also suggest that the chain
reactions in T-cell tolerance are reversible, raising the
possibility of vaccine and drug therapies that
break through the blocked immune system.
Previous research had confirmed that myeloid-derived
suppressor cells, produced in the bone
marrow, were attracted to tumors, but until now, scientists
had not identified exactly how the cells
inhibit the immune system's ability to mount an attack.
By explaining some of the precise biological workings
of myeloid-derived suppressor cells in
cancer, the team's findings suggest why experimental cancer
vaccines have to date been plagued by T-cell tolerance, a
weakened rather than strengthened immune response, says
Jonathan Schneck, one of
the study's authors.
"Our findings also open up a new door in drug and
vaccine development that we never knew
existed and provide another opportunity for drug
development into autoimmune diseases, where the
immune system is in overdrive and needs to be slowed down,"
said Schneck, a professor of medicine,
pathology and oncology at the
Johns Hopkins School of Medicine and its Kimmel
Cancer Center.
The team's latest report built on research initially
conducted at the University of South
Florida, where researchers analyzed blood samples and lymph
tissue from healthy mice injected with
myeloid-derived suppressor cells and found that T-cell
levels remained the same, indicating that
MDSCs did not destroy the immune response but apparently
altered how the T cells behaved.
Using chemical tests in which individual tumor cells
can be tagged with a fluorescent dye that
allows them to glow when they are not bound to T cells,
Florida researchers measured the immune
response in mice to various foreign proteins, with and
without injections of myeloid-derived
suppressor cells. They found an 80 percent suppression of
the immune response in the presence of
MDSCs, confirming that the suppressor cells were
inactivating the T cells.
The Florida team then turned to Schneck, who in 1993
developed several novel proteins to test
how various antigens, such as those on cancer cells,
specifically latch on to T cells.
Researchers then began experiments to determine if the
myeloid-derived suppressor cells' T-
cell interference was simply genetic or had some
biochemical explanation, testing a half-dozen major
reactions known to occur during infection to see if any set
path was particularly active during
interference.
In tissue tests from tumor-filled mice bred to lack a
biochemical reaction, the scientists found
that one specific pathway, the reactive-oxygen species, or
ROS pathway, stood out, because when
inactivated, T-cell tolerance did not develop. Researchers
were surprised when subsequent tests
showed that ROS actually modified the T cells, altering
their structure so they could no longer bind to
tumor-cell antigens.
When a known byproduct of ROS, the chemical
peroxynitriate, was neutralized, T-cell tolerance
failed to develop in test tube studies, pinning down
peroxynitrate as the culprit prohibiting immune
cell binding to and marking of "foreign" tumor cells.
"Peroxynitrate activity is the escape hatch, and now
that we have identified it, we can try to
cut it off before T-cell tolerance develops, or you can
reverse it," Schneck said.
Plans are under way to investigate the binding
receptors of MDSCs and different anti-cancer
drugs for their ability to lower levels of MDSCs and to
explore the role of MDSCs in suppressing the
immune response to stress, bacterial and viral infections,
organ transplantation and autoimmune
diseases. The researchers' goal, they say, is to find some
means of accelerating or slowing down T-cell
activity gone awry.
Study support was provided with funding from the
National Institute of Allergy and Infectious
Diseases, and the National Cancer Institute, both members
of the National Institutes of Health.
Study co-authors are Kapil Gupta, of Johns Hopkins;
Srinavas Nagaraj, Loveleen Kang, Donna
Herber and Dimitry I. Gabrilovich, of the H. Lee Moffitt
Cancer Center at the University of South
Florida; and Vladimir Pisarev, Leo Kinarsky and Simon
Sherman, of the University of Nebraska Medical
Center and Eppley Cancer Center. Gabrilovich was the study
senior author.
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