New Way to Block Cancer Immunosuppression Developed

In a new study, Belgian researchers elucidated the three-dimensional structure of a protein complex that suppresses immune responses on the cell surface. They also discovered how antibodies can block this protein complex and its downstream induced immunosuppression. Such antibodies may be used to activate an immune response against tumor cells in cancer patients, thereby triggering immune cells to destroy the tumor. The results of the study were published online in the Science, entitled “Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells”.


Immunosuppression through a series of interactions


Regulatory T cells (Treg) are immunosuppressive cells that, under normal conditions, resist excessive immune responses in the body to prevent autoimmune diseases. However, in cancer patients, they play a detrimental role by inhibiting the immune response against tumor cells. Treg cells exert their effects by producing a messenger protein called TGF-β. This messenger transmits an inhibitory signal to nearby immune cells, especially those that should destroy tumors in cancer patients.


The manner in which Treg cells produce TGF-β is complex and finely regulated because TGF-β is very efficient and must be tightly controlled. Three years ago, Professor Sophie Lucas of the de Duve Institute of the UCLouvain and her team found that TGF-β is released from a protein called GARP present on the surface of Treg cells. In collaboration with Belgian biotechnology company Argenx, the Lucas team also found that it is possible to block the release of TGF-β from GARP using specific antibodies. However, these specific antibodies are rare and often difficult to obtain. The next step is to figure out how GARP regulates the production of TGF-β and how antibodies block its release.



Elucidating molecular mechanisms


To solve these problems, the Lucas team and Argenx collaborated with Prof. Savvas Savvides and his team at the UGent Inflammation Research Center of the Flanders Institute for Biotechnology (VIB) in Belgium, resolved the three-dimensional structure of a protein complex assembled by GARP and TGF-β.


These researchers used X-ray crystallography, which has been used to study molecular structures for more than a century, and scientists are still improving it to study biomacromolecules at atomic resolution.


However, the practical problem they face is that they cannot easily obtain crystals of the GARP/TGF-β protein complex. Under the leadership of Dr. Stéphanie Lienart of the University of Leuven in Belgium and Dr. Romain Merceron of VIB-UGent, the Lucas team and the Savvides team used a blocking antibody to stabilize the structure of this protein complex—this successful approach not only helps to generate the right crystal to resolve its structure, but also provides details on how a therapeutic antibody works.


Savvides said, “We found that the structure of GARP is similar to a horseshoe, and TGF-β sits on this horseshoe structure. These two molecules are so complexly assembled that TGF-β itself helps to promote the horseshoe structure of GARP. In this protein complex, this blocking antibody binds to GARP and TGF-β. It seems to bind the two protein molecules together to ensure that when other molecules pull part of the protein complex, the smaller active part of TGF-β is not released, thus preventing it from transmitting its inhibition information.”


Lucas said, “Visual observation of this macromolecular protein complex demonstrates that it is feasible to block the activity of TGF-β released from precisely defined and restricted cell sources such as Treg cells. This can lead to the development of highly specific methods (most notably cancer immunotherapy), to treat a variety of diseases associated with changes in TGF-β or Treg cell activity.”





Stéphanie Liénart, Romain Merceron, Christophe Vanderaa et al. Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells. Science, Published Online: 25 October 2018, doi:10.1126/science.aau2909.

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