Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression
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Published:2022-01-10
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Cheung Phyllis F., Yang JiaJin, Fang Rui, Borgers Arianna, Krengel Kirsten, Stoffel Anne, Althoff Kristina, Yip Chi WaiORCID, Siu Elaine H. L., Ng Linda W. C., Lang Karl S., Cham Lamin B., Engel Daniel R., Soun Camille, Cima IgorORCID, Scheffler Björn, Striefler Jana K., Sinn Marianne, Bahra Marcus, Pelzer UweORCID, Oettle Helmut, Markus Peter, Smeets Esther M. M., Aarntzen Erik H. J. G., Savvatakis Konstantinos, Liffers Sven-Thorsten, Lueong Smiths S., Neander Christian, Bazarna Anna, Zhang Xin, Paschen Annette, Crawford Howard C., Chan Anthony W. H., Cheung Siu TimORCID, Siveke Jens T.ORCID
Abstract
AbstractImmune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.
Funder
Deutsche Forschungsgemeinschaft Ministry of Education, Culture, Sports, Science and Technology Wilhelm Sander-Stiftung Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund Deutsche Krebshilfe
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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