Restoring their proper role holds promise for new approach to therapy
Left to right: Dharminder Chauhan, JD, PhD; Ajita Singh, PhD; Kenneth Anderson, MD
Multiple myeloma cancer cells thwart many of the drugs used against
them by causing nearby cells to turn traitor — to switch from defending
the body against disease to shielding the myeloma cells from harm —
Dana-Farber Cancer Institute scientists report in the October issue of Cancer Cell.
The researchers found that immune-system cells known as plasmacytoid
dendritic cells (pDCs) essentially assume a new identity in the presence
of myeloma — promoting the growth and survival of malignant myeloma
cells, helping them fend off drugs, and depleting the overall strength
of the immune system.
The discovery not only helps explain a little-understood aspect of
myeloma biology, but also suggests a new angle of attack on the disease.
Researchers found that compounds that alight on specific sites on pDCs
restore the cells' original disease-fighting character and remove a
trigger of myeloma cell growth.
"Our study found an unusually large number of pDCs in the bone marrow
of multiple myeloma patients," says Dharminder Chauhan, JD, PhD, of
Dana-Farber, who co-led the study with Ajita Singh, PhD.
"pDCs are known to be immune system 'effector' cells — the first
responders of the body's attack on disease. But why are they present in
such abundance in myeloma patients' marrow?"
The focus on immune system cells exemplifies a new approach to the study of multiple myeloma,
a cancer of bone marrow tissue that, despite numerous treatment
advances in recent years, remains incurable. Diagnosed in 15,000
Americans a year, it accounts for just 2 percent of cancer-related
deaths, but is the fourth fastest-growing cancer in terms of mortality
and is one of the top 10 causes of death in African-Americans.
The disease's ability to resist even the latest drugs has prompted
scientists to look more closely at the basic biology of the disease,
particularly the interactions between myeloma cells and their cellular
In the current study, Chauhan and his colleagues zeroed in on those
interactions in experiments involving laboratory-grown samples of
myeloma cells and animals with the disease. They found that when pDCs
latch onto myeloma cells, a mutual release of proteins affects both sets
In myeloma cells, these proteins cause a spurt of growth. In the
pDCs, the effect is something like that of a police officer bribed to
join a gang of hoodlums. The cells abandon their role as immune system
sentinels and become the protectors of myeloma cells.
"This is the first time that immune system cells have been found to
be converted to another function," says Chauhan, who is also a principal
associate in medicine at Harvard Medical School. Investigators don't
yet know how the conversion occurs, but they suspect the proteins cause a
different set of genes to be activated within the pDCs.
Encouragingly, it appears possible to awaken errant pDCs to their
proper duty. Researchers found that when compounds known as CpG ODNs
(cytosine phosphate guanine oligodeoxynucleotides) attach to key
receptors on the surface of pDCs, the cells resume their normal immune
system function and stop spurring myeloma cell growth.
Some CpG ODNs are already in clinical trials for other forms of
cancer, and Chauhan and his colleagues hope to begin trials of the
compounds in myeloma patients soon.
"In addition to drugs that destroy cancer cells themselves,
treatments for multiple myeloma may also agents that target the immune
system's role in the disease," Chauhan says. "Our findings show the
promise of this approach."
Adds the study's senior author, Kenneth Anderson, MD, of Dana-Farber,
"This is a potential approach to the treatment of myeloma that is
refractory to all current therapies, while increasing immune function
and thereby decreasing infections in myeloma patients."
Co-authors include Mohan Brahmandam, Ruben Carrasco, Madhavi Bandi,
Teru Hideshima, MD, PhD, Giada Bianchi, Klaus Podar, MD, PhD, Yu-Tzu
Tai, PhD, Constantine Mitsiades, MD, Noopur Raje, MD, and Paul
Richardson, MD, of Dana-Farber; David Jaye, MD, of Emory University;
Shaji Kumar, MD, of the Mayo Clinic; and Nikhil Munshi, MD, of the
Veterans Administration Healthcare System in Boston.
Funding for the study was supplied by grants from the National Institutes of Health and the Myeloma 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), a designated comprehensive cancer center by the National