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Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours

时间:2019-04-08 11:38:01 阅读数:0

Recently, a research paper entitled Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumors was published by Xu Jie, Institute of Digestion, Renji Hospital Affiliated to Medical College of Shanghai Jiaotong University in the Journal Nature Biomedical Engineering. This paper reports the mechanism of palmitoylation modification of PD-L1 to promote its expression. The designed PD-PALM polypeptide reduces the expression of PD-L1 in cancer cells, and develops a target polypeptide molecule that can compete to inhibit palmitoylation of PD-L1. It provides a new idea for the development of immunological checkpoint inhibitors. The target polypeptide molecule is hopeful to become a cancer immunotherapy drug through optimization.

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(Title and author information)

While the paper was published online, a review by Professor Stephane Lefrancois, a senior expert in cell biology, explained in detail the scientific findings and significance of this work. It was concluded that "blocking palmitoylation of PD-L1 with polypeptide inhibitors suggests a new targeting method based on post-translational modification. The cell-penetrating polypeptide developed by Xu Jie's team significantly inhibits PD-L1, and thus may have potential as a therapeutic molecule."(The use of a peptide inhibitor to block the palmitoylation of PD-L1 highlights the potential of silencing this post-translational modification for therapeutic purposes. The cell-penetrating peptide developed by Xu and colleagues leads to efficient PD-L1 suppression and could potentially be used as a therapeutic agent.)

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(Expert Review of Periodical Distribution)

 

Immune checkpoints are inhibitory signaling pathways distributed in the body's immune system, which can regulate the intensity and duration of immune response, avoid tissue damage and maintain the tolerance of the body itself. Tumors can use the inhibitory effect of immune checkpoint pathway to avoid the identification of epidemic cells, especially to inhibit the immune response of T cells, so as to achieve immune escape. Therefore, suppression of immune checkpoints can stimulate the original anti-tumor ability of the immune system. Monoclonal antibodies targeting immune checkpoint proteins CTLA-4 and PD-1/PD-L 1 have been approved for the treatment of various types of malignant tumors.

However, immune checkpoint blocking therapy still has some problems, such as low overall efficiency, drug resistance and serious side effects after long-term use. PD-L1 is the main ligand of PD-1. Some tumors depend on its expression of PD-L1 to bind to PD-1 on T surface and cause T cell failure, which prompts tumors to evade the surveillance and killing effect of host immune system. Therefore, further study on the regulation mechanism of PD-L1 will help to improve the therapeutic effect. Recent studies have found that PD-L1 is not only expressed on the cell surface, but also on the intracellular Golgi apparatus, circulatory endosomes and microcapsules, and that intracellular PD-L1 can promote cancer and can be re-transported to the cell surface. Therefore, targeted protein degradation strategies aiming at the complete elimination of PD-L1 have attracted much attention. Xu Jie's team recently discovered the lysosome degradation mechanism of PD-L1, and designed PD-LYSO to target the degradation of PD-L1 (Nature Chemical Biology 2019) inspired by the regulation model of HIP1R protein.

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(The mechanism of palmitoylation of PD-L1 and the mode of action of polypeptide inhibitor PD-PALM revealed)

 

Xu Jie's team found that PD-L1 protein could be palmitoylated by DHHC3, and reduced its ubiquitination and lysosome degradation. The elucidation of this mechanism will provide inspiration for the development of PD-L1 inhibitors. Due to the lack of selectivity of small molecule inhibitors of palmitoylation to DHHC enzyme, Xu Jie's team has made an attempt to design competitive palmitoylation inhibitors. Because the specificity of DHHC is determined by the substrate sequence, the adjacent sequence of the modified site of PD-L1 may be modified by DHHC3, thus reducing the modification of endogenous PD-L1. In theory, this competitive polypeptide has less influence on other DHHC members, so its selectivity may be stronger than that of 2-BP. Through a series of experiments, the authors proved that the design idea of the competitive inhibitors was effective, and the expression of PD-L1 in cancer cells was reduced by the designed PD-PALM polypeptide. On this basis, PD-PALM can be further modified and modified in order to further improve its activity and stability and enhance its pharmaceutical potential.

This study explored the function and mechanism of palmitoylation of PD-L1, revealed the exact pathway of palmitoylation affecting lysosome degradation of PD-L1, and designed polypeptide-based PD-L1 inhibitors targeting palmitoylation, which could provide inspiration for palmitoylation-related mechanisms and transformation research.

The communication author of this paper is Xu Jie, the first author is Dr. Yao Hao, the co-first author is Dr. Lanjiang, Dr. Li Chushu and Professor Shi Hubing. The project is supported by the National Key Research and Development Program and the National Natural Science Foundation of China.

 

About Xu Jie

Researcher and doctoral supervisor of Renji Hospital Affiliated to Shanghai Jiaotong University Medical College, Ph.D. graduated from Brussels Free University, Belgium. He is mainly engaged in the study of the mechanism of digestive system tumorigenesis and biological therapy targets. He also conducts research on the mechanism and transformation of PD-1/PD-L1 tumor immune checkpoint and p53 anti-cancer pathway. He has been selected as the National Outstanding Natural Youth Program, Top Young Talents of the Ten Thousands Program, Zhongying Scholars and Oriental Scholars Program. He undertakes many research projects such as national key R&D projects and Natural Science Foundation. He is also the deputy editor of BMC Cancer and the chief editor of Frontiers in Pharmacology. In recent years, he has published papers in journals such as Nature Chemical Biology, Nature Biomedical Engineering, Cell Chemical Biology, Gut, JNCI, Cancer Research, Nature Communications, Cell Reports, Oncogene and so on.

 

Paper links:

https://www.nature.com/articles/s41551-019-0375-6


From: Shanghai Jiaotong Univercity