TGF-beta is a cytokine, or secreted protein, that controls the cell
cycle and is used by regulatory T cells (Tregs) as a signal to tell
immune cells not to attack normal cells in the body. However, TGF-beta
has become a widely studied cancer cytokine.
Malignant tumors release
large amounts of TGF-beta, which allows cancer cells to divide rapidly
and to push Tregs to suppress immune cells that fight them. It has been
uniquely difficult to design therapies that block TGF-beta, mainly
because healthy cells cannot function without it.
‘An antibody-based therapy that could target the functions of TGF-beta that cause cancer has been designed by scientists.’
Scientists at the Medical University of South Carolina (MUSC) have
designed an antibody-based therapy that could target the functions of
TGF-beta that cause cancer. The therapy targets TGF-beta where it is
particularly dangerous - docked on the surface of tumor cells.
The team began by examining how TGF-beta grows out of control in the
first place, according to Zihai Li, chair of the
Department of Microbiology and Immunology at the MUSC Hollings Cancer
Center and principal investigator on the project. "TGF-beta is an old
story. The new spin is that there is a docking receptor for TGF-beta
that increases the activity of the cytokine, and this molecule is called
GARP," said Li.
Enter GARP. GARP is the only known receptor that allows TGF-beta to
dock on the surface of cells. In this way, GARP helps cells to store
TGF-beta. Importantly, Li knew that GARP could bind and activate
TGF-beta and then float off the surface of cells that express it. Could
this be a way that cancer cells store and release TGF-beta? The Li
laboratory decided to find out.
In the December 15, 2016 issue of Cancer Research
, Li and
his colleagues, including first author and student Alessandra Metelli,
report that levels of GARP were much higher in biopsies of human breast,
lung, and colon tumors than in normal tissue. With this finding, it was
reasonable to hypothesize that these higher levels of GARP provided
more storage capacity for the TGF-beta needed for enhanced tumor growth.
To examine if GARP had a direct role in cancer development, the MUSC
team next deleted the gene for GARP from mice with mammary tumors and
found that, without GARP, breast cancer tumors grew more slowly and were
less able to metastasize to the lungs. Further experiments showed
increased TGF-β signaling, tumor growth, and metastasis after the gene
for GARP was inserted into mouse mammary tumor cells expressing high
levels of GARP. Mice with more GARP also had more TGF-beta-releasing
Treg cells. This meant that GARP promoted both cancer-intrinsic
(metastasis) and -extrinsic (immune suppression) effects in breast
These were the first clues that GARP could be a diagnostic marker
for cancer, according to Li. It also created an opportunity to develop
The MUSC team immunized mice with human GARP in order to grow
antibodies that could potentially block it. Only one antibody, 4D3,
directly blocked human TGF-beta from binding to GARP expressed on cell
surfaces. While 4D3 did not prevent growth of primary mammary tumors in
mice, it did suppress the spread of these tumors to their lungs.
However, 4D3 combined with cyclophosphamide chemotherapy curbed both
primary tumor growth and metastasis. This means that combination
immunotherapy with GARP antibody might boost the effectiveness of
standard chemotherapy in breast cancer.
Li acknowledged that blocking GARP might also block the natural
ability of Tregs to suppress the immune system, which could potentially
lead to inflammatory autoimmune reactions. "Clinically some of the
proven immunotherapies do induce some degree of autoimmunity," he said.
"When cancer is cured and patients stop immunotherapy, the autoimmune
manifestations completely disappear as well."
An accurate biomarker for GARP could offer an opportunity for
earlier detection of other aggressive cancers, given that GARP levels
increase before metastasis, according to Li. As part of their work, the
group also showed that life expectancy was decreased in patients with
colon or lung cancer whose biopsied tissues showed high levels of GARP.
The challenge resides in the development of an antibody accurate enough
to detect it in humans with cancer.
There have been great advances in cancer immunotherapies in the past
decade, but there is still vast room for improvement. GARP suppression
represents a novel addition to established cancer immunotherapies that
also use antibodies to wake up the immune system to fight cancer.
"This discovery is fundamentally important to how TGF-beta utilizes
GARP to promote cancer and down-regulate the immune system, but it also
creates an opportunity for both diagnostics and therapeutics," said Li.
From the perspective of Li and his colleagues at the MUSC Hollings
Cancer Center, they have only just scratched the cell surface.