St. Jude Children’s Research Hospital scientists used a novel strategy to
find the white blood cells that tumors rely on to suppress the immune
response; results provide foundation for efforts to improve
immunotherapy.
A study led by St. Jude Children’s Research Hospital scientists has
identified the population of white blood cells that tumors use to
enhance growth and suppress the disease-fighting immune system. The
results, which appear in the December 18 edition of the scientific
journal Immunity, mark a turning point in cancer immunology and provide the foundation for developing more effective immunotherapies.
For years, researchers have known that a diverse group of white blood
cells called myeloid-derived suppressor cells (MDSC) are more abundant
in cancer patients than in healthy individuals. The cells enhance cancer
growth and suppress the specialized T cells that target and destroy
tumor cells. MDSCs have a common origin in the bone marrow, but leave to
travel throughout the body and become immune cells with different
functions. Blocking T cells is one of the main MDSC functions.
Until now, however, efforts to distinguish among the cell types and
identify the population responsible for anti-tumor immune suppression
have fallen short. The puzzle has hampered efforts to harness the immune
system to fight disease.
Working in the laboratory and in mouse models of cancer, researchers
on this study showed immune suppression associated with MDSCs is
primarily the work of a type of white blood cells called monocytes.
Monocytes give rise to macrophages that help clean up dead or damaged
tissue, fight cancer and regulate the immune response.
"We have identified the monocytic cells as the important cell to
target, not only in cancer but possibly for treatment of autoimmune
disorders like rheumatoid arthritis or inflammatory bowel diseases where
dampening the immune response could provide relief," said corresponding
author Peter Murray, Ph.D., a member of the St. Jude departments of
Infectious Diseases and Immunology. "We also identified growth factors
and other molecules essential to the survival and function of these
monocytic cells. Targeting these molecules could lead to more precise
approaches for controlling the immune response at the tumor site.
"This study marks a significant step in efforts to understand,
develop and optimize immunotherapies for treatment of cancer," he said.
Murray’s interest in MDSCs dates to 2008 and coincided with research
from other St. Jude investigators. Their studies provided insight into
regulation of two forms of programmed cell-death pathways known as
apoptosis and necroptosis. Cells use the pathways to get rid of damaged,
dangerous or unneeded cells.
From the laboratory of co-author Joseph Opferman, Ph.D., an associate
member of the St. Jude Department of Cell and Molecular Biology, came
evidence that switching off the MCL1 gene in bone marrow led to
the death of granulocytes, but not monocytes, via apoptosis. Then work
from Douglas Green, Ph.D., chair of the St. Jude Department of
Immunology, highlighted the protein FLIP as a key regulator of both
apoptosis and necroptosis. Selectively eliminating FLIP in mice resulted
in an over-abundance of granulocytes and a reduction in monocytes and
related cells.
In this study, researchers selectively eliminated MCL1 or FLIP to
track how the loss of granulocytes or monocytes affected T cells in the
laboratory and in mouse models of neuroblastoma and other cancers. The
results showed that monocytic cells are primarily responsible for T cell
suppression around tumors. Scientists are still determining the role of
the granulocytes in tumors.
"We've known for decades that cancer has harnessed the immune system
to keep pumping out large numbers of mature and immature myeloid cells
from the bone marrow," Murray said. "Collaborating with the Opferman and
Green laboratories gave us the tools we need to discriminate between
the cell populations and identify monocytic cells as the important cells
to target with immunotherapies."
The work also provided new details of how FLIP, MCL1 and the
MCL1-like protein A1 work together to ensure survival of the monocytic
population of MDSCs. For example, FLIP blocks programmed cell death via
apoptosis and necrosis, but researchers showed that survival of
monocytic cells required inhibition of just the apoptotic pathway.
Investigators also identified the growth factor that regulates
production of A1, which in the absence of MCL1 can block the death of
monocytes by blocking one of the cell death pathways.
The first author is Jessica Haverkamp, Ph.D., a postdoctoral fellow
in Murray’s laboratory. The other authors are Amber Smith, Ricardo
Weinlich, Christopher Dillon, Geoffrey Neale and Brian Koss, all of St.
Jude; Joseph Qualls, formerly of St. Jude; Young Kim, Johns Hopkins
School of Medicine, Baltimore; Vincenzo Bronte, Verona University
Hospital and Department of Pathology, Verona, Italy; and Marco Herold,
Walter and Eliza Hall Institute of Medical Research, Victoria,
Australia.
The research was funded in part by the Hartwell Foundation, Alex’s
Lemonade Stand Foundation, a grant (CA21765) from the National Cancer
Institute at the National Institutes of Health and ALSAC.