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. The antibodies may be used to activate the immune response against tumor cells in cancer patients, thereby triggering immune cells to destroy the tumor. The results of the study were published in Science on October 25, 2018, entitled "Structure based on potential TGF-β1 expression and GARP activation of human regulatory T cells."
Regulatory T cells (Tregs) 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 way which Treg cells produce TGF-β is complex and finely regulated because TGF-β is very efficient and must be tightly controlled.
3 years ago, the researchers found that TGF-β is released from a protein called GARP on the surface of Treg cells. It is possible to block the release of TGF-β from GARP using specific antibodies.
The researchers resolved the three-dimensional structure of a protein complex assembled by GARP and TGF-β. The structure of GARP is similar to horseshoe, and TGF-β straddles this horseshoe structure. The two molecules are assembled so complexly that TGF-β itself contributes to the formation of the horseshoe-shaped 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 a part of the protein complex, the smaller active part of TGF-β is not released, preventing it from transmitting its inhibitory information.