by Sver Aune
Alessandra Metelli (left) and Dr. Zihai Li (right)
Cancer immunologists at MUSC have designed an antibody-based therapy that targets the cancer cytokine TGF-beta where it could be particularly dangerous. The group reported in the December 15, 2016 issue of Cancer Research that the antibody binds a receptor called GARP, which stores TGF-beta on the surface of tumor cells.
The work started by considering how cancer cells use TGF-beta as a disguise from the immune system, according to Zihai Li, M.D., Ph.D., chair of the Department of Microbiology and Immunology and a member of the MUSC Hollings Cancer Center. In healthy cells, TGF-beta is a secreted protein that is used by regulatory T cells (Tregs) as a signal to tell immune cells not to attack normal cells in the body. Malignant tumors mask their presence by releasing large amounts of TGF-beta to neutralize the immune cells that would attack them.
“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,” says Li.
GARP is the only known receptor that allows TGF-beta to dock on the surface of cells. 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 laboratory set about finding out.
Li and his colleagues, including first author and student Alessandra Metelli, first noticed that GARP expression was much higher in biopsies of human breast, lung and colon tumors than in normal tissue. To examine if GARP had a direct role in cancer development, they deleted the gene for GARP from mice with mammary tumors. The tumors grew slower and were less able to metastasize to the lungs. When the GARP gene was inserted into mouse mammary cells, they revealed increased TGF-beta signaling, tumor growth and metastasis. Mice with more GARP also had more TGF-beta-releasing Tregs. This meant that GARP enabled both cancer metastasis and immune suppression effects in breast cancer.
These were the first clues that GARP could be a diagnostic marker for cancer. It also created an opportunity to develop new treatments.
The laboratory immunized mice with human GARP in order to grow antibodies that could potentially block it. Only one antibody, 4D3, 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 acknowledges 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 says. “When cancer is cured and patients stop immunotherapy, the autoimmune manifestations completely disappear as well.”
GARP suppression represents a novel addition to established cancer immunotherapies that also use antibodies to wake up the immune system to recognize and fight cancer. The study has drawn interest from industry partners to bring the antibody to clinical trials.