Programmed cell death protein 1 (PD-1), is a protein found on the surface of cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes. Second, it reduces apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells)The PD-1 pathway, consisting of the co-inhibitory receptor PD-1 on T cells and its ligand (PD-L1) on antigen-presenting cells (APCs), is a major mechanism of tumor immune evasion. PD-1 and PD-L1 blockade antibodies have produced remarkable clinical activities against a subset of cancers. Binding between T cell-intrinsic PD-1 and APC-intrinsic PD-L1 triggers inhibitory signaling to attenuate the T cell response.
It is challenging to determine whether PD-L1 and PD-1 bind in cis on the same cell membrane, and if so, what is the functional consequence. This is because of the co-existence of cis and trans interactions at the cell–cell interface. Methods to decouple cis and trans-interactions are urgently needed.
Dr Enfu Hui and associates from UC San Diego have developed methods to decouple cis and trans-interactions: cellular and cell-free reconstitution methods to reveal that PD-L1, a key weapon of used by tumor cells to escape immune destruction, can be neutralized by its own receptor PD-1 expressed on the same cells. These methods can be applied to address whether similar neutralization mechanisms apply to other immune checkpoints, and in general any cell surface ligands or receptors.
Another key aspect of this invention is to use PD-1 blockade antibodies to decouple the cis and trans interactions between PD-L1 and PD-1. At the interface between tumor cells and immune cells, PD-L1 can bind either to PD-1 on the same cell (cis), or to PD-1 on a different cell (trans). In vivo administration of PD-1 or PD-L1 blockade antibodies would disrupt both types of interactions. The researchers also invented a “preincubation and wash” method to decouple these two modes of interactions. This allows one to address the functional consequence of either interaction. One may envision this novel method may have further application in decoupling cis and trans interactions in other signaling processes.
This technology is patent pending and available for licensing
Programmed cell death protein 1, PD1, Immune checkpoint, antibody blocking, cancer, autoimmunity