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

doi:10.1038/s41551-019-0375-6

. 2019 Apr;3(4):306-317.

doi: 10.1038/s41551-019-0375-6. Epub 2019 Mar 25.

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

Han Yao¹, Jiang Lan², Chushu Li¹, Hubing Shi², Jean-Philippe Brosseau³, Huanbin Wang¹, Haojie Lu⁴, Caiyun Fang⁴, Yao Zhang¹, Lunxi Liang^{1

5}, Xiaolin Zhou⁶, Chaojun Wang⁷, Yu Xue⁸, Yun Cui¹, Jie Xu⁹

Affiliations

¹ State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² 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.
³ Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁵ Department of Gastroenterology, Changsha Central Hospital, Changsha, China.
⁶ Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁷ Urology Department, The First Affiliated Hospital of Zhejiang University, Zhejiang, China.
⁸ Department of Bioinformatics & Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
⁹ State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jiexu@yahoo.com.

PMID: 30952982
DOI: 10.1038/s41551-019-0375-6

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

Han Yao et al. Nat Biomed Eng. 2019 Apr.

. 2019 Apr;3(4):306-317.

doi: 10.1038/s41551-019-0375-6. Epub 2019 Mar 25.

Authors

Affiliations

¹ State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² 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.
³ Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁵ Department of Gastroenterology, Changsha Central Hospital, Changsha, China.
⁶ Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁷ Urology Department, The First Affiliated Hospital of Zhejiang University, Zhejiang, China.
⁸ Department of Bioinformatics & Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
⁹ State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jiexu@yahoo.com.

PMID: 30952982
DOI: 10.1038/s41551-019-0375-6

Erratum in

Author Correction: Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours.
Yao H, Lan J, Li C, Shi H, Brosseau JP, Wang H, Lu H, Fang C, Zhang Y, Liang L, Zhou X, Wang C, Xue Y, Cui Y, Xu J. Yao H, et al. Nat Biomed Eng. 2019 May;3(5):414. doi: 10.1038/s41551-019-0402-7. Nat Biomed Eng. 2019. PMID: 30976071

Abstract

Checkpoint blockade therapy targeting the programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 promotes T-cell-mediated immunosurveillance against tumours, and has been associated with marked clinical benefit in cancer patients. Antibodies against PD-L1 function by blocking PD-L1 on the cell surface, but intracellular storage of PD-L1 and its active redistribution to the cell membrane can minimize the therapeutic benefits, which highlights the importance of targeting PD-L1 throughout the whole cell. Here, we show that PD-L1 is palmitoylated in its cytoplasmic domain, and that this lipid modification stabilizes PD-L1 by blocking its ubiquitination, consequently suppressing PD-L1 degradation by lysosomes. We identified palmitoyltransferase ZDHHC3 (DHHC3) as the main acetyltransferase required for the palmitoylation of PD-L1, and show that the inhibition of PD-L1 palmitoylation via 2-bromopalmitate, or the silencing of DHHC3, activates antitumour immunity in vitro and in mice bearing MC38 tumour cells. We also designed a competitive inhibitor of PD-L1 palmitoylation that decreases PD-L1 expression in tumour cells to enhance T-cell immunity against the tumours. These findings suggest new strategies for overcoming PD-L1-mediated immune evasion in cancer.

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Comment in

Tumour suppression by blocking palmitoylation.
Lefrancois S. Lefrancois S. Nat Biomed Eng. 2019 Apr;3(4):255-256. doi: 10.1038/s41551-019-0383-6. Nat Biomed Eng. 2019. PMID: 30952983 No abstract available.

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

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

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