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

Phyllis F. Cheung, Jia Jin 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 PelzerHelmut 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, Jens T. Siveke

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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.

Original languageEnglish
Article number156
JournalNature Communications
Issue number1
StatePublished - Dec 2022
Externally publishedYes


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