VUMC researchers: Blood cells aid tumor growth
P. Charles Lin, Ph.D., (foreground), and his colleagues (from left) Li Yang, Ph.D., David P. Carbone, M.D., Ph.D., and Laura M. DeBusk were among the VUMC researchers who found a new connection between immune suppression and tumor blood vessel growth. The finding could lead to new cancer treatments. (photo by Dana Johnson)
A blood cell that helps tumors escape from the immune system also aids in construction of new blood vessels essential for tumor growth, researchers at Vanderbilt University Medical Center have found.
This so-called myeloid immune suppressor cell is a potential new target for therapies aimed at stopping or preventing tumor growth, the researchers reported in a paper featured this week on the cover of the journal Cancer Cell.
“We have identified new functions in myeloid immune suppressor cells — these cells directly promoted tumor angiogenesis (blood vessel growth),” said P. Charles Lin, Ph.D., the paper’s senior author. “We think this will have great implications for cancer therapy.”
Targeting these cells, for example, could simultaneously improve the effectiveness of cancer “vaccines” and inhibit angiogenesis, said Lin, assistant professor of Radiation Oncology, Cancer Biology and Cell & Developmental Biology.
Myeloid immune suppressor cells are produced in the bone marrow in a very small numbers, and normally mature into dendritic cells, one of the “sentinel” cells of the immune system. Dendritic cells can stimulate another type of white blood cell, called the “T” lymphocyte, to attack foreign material, including tumor cells.
In the presence of the tumor, however, myeloid immune suppressor cells are over-produced and they don’t mature into dendritic cells. Instead, they block the ability of T cells to recognize and attack tumor cells (thus their name). This may explain why immature cells are found in large numbers in patients with advanced cancer, and why cancer vaccines have failed to stimulate an immune response in these patients.
One of Lin’s co-authors, David P. Carbone, M.D., Ph.D., Ingram Professor of Cancer Research and professor of Medicine and Cancer Biology, has made major contributions to understanding the effects of VEGF on the immunological function of these cells. But until now it was unclear whether these cells played other roles in tumor growth.
In the current study, Lin and his colleagues made four novel findings:
• Myeloid immune suppressor cells infiltrated tumors in mice.
• They produced matrix metalloproteinase 9 (MMP9), an enzyme that can break down the extracellular matrix in tumors, and which can “switch on” production of VEGF and facilitate growth of new blood vessels.
• They also differentiated into endothelial cells, and thus became part of the new blood vessels that fed tumor growth. “This is really a dynamic process,” Lin said. “The same cells can do multiple functions, depending on the environment.”
• In the bone marrow, myeloid immune suppressor cells also produced MMP9, which releases the sKit ligand, a factor that facilitates production and mobilization of more of these immature cells.
These findings provide an explanation for the observation that myeloid immune suppressor cells are over-produced in patients with advanced cancer.
Like other immune cells, myeloid immune suppressor cells can travel through tissues and into tumors. “Apparently tumors take advantage of this property to recruit them to the tumor site, then reprogram them for the benefit of tumor growth,” Lin says. “This, in fact, is a conspiracy by tumors to subvert the host.”
This ability of the tumor microenvironment to reprogram myeloid immune suppressor cells is very important in understanding tumor-host interactions. Approaches designed to eliminate myeloid immune suppressor cells not only could improve the body’s immune response against tumors but also may block the development of blood vessels that feed them, the Vanderbilt researchers concluded.
The lead author of the study was Li Yang, Ph.D., a graduate student in Cancer Biology who recently earned her doctorate. Other contributors include Lynn Matrisian, Ph.D., chair of Cancer Biology, Laura M. DeBusk, Koari Fukuda, M.D, Ph.D., Barbara Fingleton, Ph.D., Brenda Green-Jarvis, Ph.D. and Yu Shyr, Ph.D.
The research was supported by the National Cancer Institute and by Vanderbilt’s Specialized Programs of Research Excellence in lung and gastrointestinal cancers.