Researchers hope to knock out molecular "bodyguard" that helps Hodgkin cells survive
Margaret Shipp, MD
Dana-Farber Cancer Institute scientists have identified a protein
that prevents the body's immune system from recognizing and attacking
Hodgkin lymphoma cells. Based on this finding, the researchers are now
investigating targeted therapies to disable this molecular "bodyguard"
and boost a patient's ability to fight the blood cancer.
If the strategy proves successful, patients might escape some of the
long-term complications – like heart damage and the threat of a second
cancer – caused by standard treatments that include radiation, said
Margaret Shipp, MD, of Dana-Farber, who headed the study. A report will
be posted online by the Proceedings of the National Academy of Sciences on July 30 and will appear in an upcoming print issue of the journal.
"We're excited about this treatment lead," said Shipp, a medical
oncologist. "We are currently generating antibodies that can neutralize
the 'bodyguard' protein, and we'd like to fast-track this experimental
therapy into clinical trials."
Nearly 8,200 people in the United States — the great majority of them
young adults — will be diagnosed with Hodgkin lymphoma in 2007,
according to the American Cancer Society, with an estimated 1,070
deaths. The cancer begins in the lymph nodes and channels that
distribute infection-fighting white blood cells around the body. Its
symptoms can include swollen glands in the neck, night sweats and
Reed-Sternberg cells (seen here as dark brown cells)
The biological trademark of Hodgkin lymphoma is a type of giant,
mutant white blood cell called the Reed-Sternberg cell that is found in
the lymph node tumors. While most solid cancers consist almost entirely
of tumor cells, says Shipp, Hodgkin tumors, which can reach the size of a
basketball, contain only about 5 percent cancerous Reed-Sternberg
cells; the rest are different types of immune cells recruited to fight
the tumor, but they are ineffective.
"You would expect with all these host immune cells attracted to the
area of the tumor cells that they would mount a great antitumor
response," Shipp says. "But that's not the case. There are a lot of
immune cells, but they're the wrong kind."
The immune army includes different types of T cells, such as T helper
1 (Th1) cells designed to recognize and kill foreign infectious agents
and sometimes tumors, T helper 2 (Th2) cells, which normally control
allergic responses, and T regulatory (Treg) cells that
suppress other T-cell types and shut down an immune response when the
job is done. The Hodgkin tumors are overloaded with Th2 and Treg cells that act as bodyguards for the cancer by weakening the Th1 immune response against it.
Jing Ouyang and Przemyslaw Juszczynski are part of a team that identified a treatment lead for Hodgkin lymphoma.
Przemyslaw Juszczynski, MD, PhD, Jing Ouyang, PhD, and colleagues
from the Shipp laboratory, together with collaborators from Brigham and
Women's Hospital, the Broad Institute and the University of Buenos
Aires, hunted for the source of the cancer cells' protection. Using gene
microarray chips, the scientists looked for genes that were active in
Reed-Sternberg cells but not in cells of another non-Hodgkin B-cell
The comparison revealed that a gene called Gal1 was up to 30
times more active in the Reed-Sternberg cells, causing them to secrete
large quantities of a protein – Gal1 or Galectin 1 – that turns down the
Th1 immune response. The Shipp team then defined the mechanism for Gal1
overexpression in Hodgkin lymphoma. Next, they demonstrated that Th1
immune cells underwent apoptosis, or cell death, when treated with Gal1,
leaving increased numbers of Th2 cells and the suppressive Treg cells. Using a gene-silencing technique, RNA interference or RNAi, they then turned off the Gal1
gene in Hodgkin Reed-Sternberg cells and showed that it blocked the
death of infiltrating normal Th1 cells, making them an equal force to
the Th2 cells.
"Likely what's happening here is that the tumor cells essentially
hijack a normal regulatory program and use it to avoid being knocked off
by the immune response," explains Shipp, who is also a professor of
medicine at Harvard Medical School. "These observations provide an
important explanation for why you have this ineffective immune response
in Hodgkin lymphoma."
She adds that this bodyguard strategy may not be limited to Hodgkin
lymphoma. One of the collaborating authors, Gabriel Rabinovich, PhD, of
the University of Buenos Aires, has blocked Gal1 in mice with a
form of the deadly skin cancer melanoma, and the animal's immune system
succeeded in eliminating the cancer, Shipp says. "We think it's very
possible that this strategy will be applicable to other types of
The study's other authors are Stefano Monti, PhD, Scott Rodig, MD,
PhD, Kunihiko Takeyama, MD, PhD, Jeremy Abramson, MD, Wen Chen, PhD, and
Jeffery Kutok, MD, PhD.
The research was funded by the Miller Family Research Foundation.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National