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A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions.

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机构： [1]Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University 145 Middle Shandong Road Shanghai 200001 China. [2]Institutes of Biomedical Sciences, Fudan University, and Zhongshan-Xuhui Hospital, Shanghai Key Laboratory of Medical Epigenetics, Fudan University Shanghai China [3]Department of Biochemistry and functional Genomics, University of Sherbrooke 3001 Jean-Mignault Sherbrooke J1E4K8 Canada. [4]Department of Chemistry and Institutes of Biomedical Sciences, Fudan University Shanghai China. [5]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center Chengdu China.

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Programmed cell death protein 1 (PD-1) is a crucial anticancer target, but the relatively low response rate and acquired resistance to existing antibody drugs highlight an urgent need to develop alternative targeting strategies. Here, we report the palmitoylation of PD-1, discover the main DHHC enzyme for this modification, reveal the mechanism of its effect on PD-1 protein stability, and rationally develop a peptide for targeting PD-1 expression. Palmitoylation promoted the trafficking of PD-1 to the recycling endosome, thus preventing its lysosome-dependent degradation. Palmitoylation of PD-1, but not of PD-L1, promoted mTOR signaling and tumor cell proliferation, and targeting palmitoylation displayed significant anti-tumor effects in a three-dimensional culture system. A peptide was designed to competitively inhibit PD-1 palmitoylation and expression, opening a new route for developing PD-1 inhibitors and combinatorial cancer immunotherapy.This journal is © The Royal Society of Chemistry.

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第一作者机构： [1]Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University 145 Middle Shandong Road Shanghai 200001 China.

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