MUSC scientists design novel antibody-based therapy to fight against cancer

MUSC scientists design novel antibody-based therapy to fight against cancer
  1. MUSC scientists design novel antibody-based therapy to fight against cancer
    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…

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, M.D., Ph.D., 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.

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.

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 cancer.

These were the first clues that GARP could be a diagnostic marker for cancer, according to Li. It also created an opportunity to develop new treatments.

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…

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