Abstract:

Xu Jie research group of digestive Institute of Renji Hospital Affiliated to Medical College of Haijiao Tong University reduced the expression of PD-L1 in tumor cells through the designed pd-palm polypeptide, and developed a target polypeptide molecule that can competitively inhibit palmitoylation of PD-L1, which provides a new idea for the development of immunosuppressant. The target polypeptide molecule is expected to become a tumor immunotherapy drug after optimization. On August 28, the reporter learned that relevant research results were published online in nature biomedical engineering.

While the paper was published online, the magazine distributed Stephane, a senior expert in the field Lefrancois's review explains the scientific findings and significance of this work in detail. It is believed that "the use of peptide inhibitors to block palmitoylation of PD-L1 suggests a new targeting method based on post-translational modification. This cell penetrating peptide developed by Xu Jie's research group significantly inhibits the expression of PD-L1 and thus may have potential to become a therapeutic molecule".

Immunocheckpoint is an inhibitory signaling pathway distributed in the immune system of the body, which can regulate the strength and duration of immune response, avoid tissue damage and maintain the tolerance of the body itself. Tumor can evade the recognition of immune cells, especially the immune response of T cells by using the inhibition of immune checkpoint pathway. Therefore, inhibition of immune checkpoint can stimulate the original anti-tumor ability of the immune system.

However, there are still some problems in immunocheckpoint blocking therapy, such as low overall efficiency, drug resistance after long-term use and serious side effects. PD-L1 is the main ligand of PD-1. Some tumors rely on its expressed PD-L1 to bind to PD-1 on t surface and cause T cell failure, which makes tumors escape the surveillance and killing effect of host immune system. Therefore, in-depth study of the regulatory mechanism of PD-L1 will help to improve the therapeutic effect. In recent years, it has been found that PD-L1 is not only expressed on the cell surface, but also on the Golgi body, circulating body and microbubbles in the cell; PD-L1 in the cell has cancer promoting function and can be transported to the cell surface again. Therefore, the target protein degradation strategy aimed to completely eliminate PD-L1 is concerned.

Xu Jie's team found that PD-L1 protein can be palmitoylated by dhhc3 enzyme, and reduce its ubiquitination and lysosomal degradation. Due to the lack of selectivity for dhhc enzyme in palmitoylation small molecular inhibitors, Xu Jie's research group has tried to design palmitoylation competitive inhibitors, and through the designed pd-palm polypeptide, the expression of PD-L1 in tumor cells has been reduced. On this basis, pd-pal can be modified and modified in the future to further improve its activity and stability, and enhance its potential as a drug, the researchers said.

This research project has been supported by the national key research and development plan and a number of National Natural Science Funds.

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