Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression

Phyllis F. Cheung, JiaJin Yang, Rui Fang, Arianna Borgers, Kirsten Krengel, Anne Stoffel, Kristina Althoff, Chi Wai Yip, Elaine H. L. Siu, Linda W. C. Ng, Karl S. Lang, Lamin B. Cham, Daniel R. Engel, Camille Soun, Igor Cima, Björn Scheffler, Jana K. Striefler, Marianne Sinn, Marcus Bahra, Uwe Pelzer, Helmut Oettle, Peter Markus, Esther M. M. Smeets, Erik H. J. G. Aarntzen, Konstantinos Savvatakis, Sven-Thorsten Liffers, Smiths S. Lueong, Christian Neander, Anna Bazarna, Xin Zhang, Annette Paschen, Howard C. Crawford, Anthony W. H. Chan, Siu Tim Cheung () and Jens T. Siveke ()
Additional contact information
Phyllis F. Cheung: University Hospital Essen
JiaJin Yang: University Hospital Essen
Rui Fang: University Hospital Essen
Arianna Borgers: University Hospital Essen
Kirsten Krengel: University Hospital Essen
Anne Stoffel: University Hospital Essen
Kristina Althoff: University Hospital Essen
Chi Wai Yip: The Chinese University of Hong Kong
Elaine H. L. Siu: The Chinese University of Hong Kong
Linda W. C. Ng: The Chinese University of Hong Kong
Karl S. Lang: University of Duisburg-Essen
Lamin B. Cham: University of Duisburg-Essen
Daniel R. Engel: University Hospital Essen
Camille Soun: University Hospital Essen
Igor Cima: German Cancer Consortium (DKTK partner site Essen/Düsseldorf)
Björn Scheffler: German Cancer Consortium (DKTK partner site Essen/Düsseldorf)
Jana K. Striefler: Haematology and Tumorimmunology
Marianne Sinn: Haematology and Tumorimmunology
Marcus Bahra: Krankenhaus Waldfriede
Uwe Pelzer: Charité University Hospital
Helmut Oettle: Praxis und Tagesklinik
Peter Markus: Elisabeth Hospital Essen
Esther M. M. Smeets: Radboud university medical Center
Erik H. J. G. Aarntzen: Radboud university medical Center
Konstantinos Savvatakis: University Hospital Essen
Sven-Thorsten Liffers: University Hospital Essen
Smiths S. Lueong: University Hospital Essen
Christian Neander: University Hospital Essen
Anna Bazarna: University Hospital Essen
Xin Zhang: University Hospital Essen
Annette Paschen: University Hospital Essen, University of Duisburg-Essen
Howard C. Crawford: University of Michigan
Anthony W. H. Chan: The Chinese University of Hong Kong
Siu Tim Cheung: The Chinese University of Hong Kong
Jens T. Siveke: University Hospital Essen

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Immune 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.

Date: 2022
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-27088-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27088-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-27088-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().