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
  • Jens T Siveke


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.

Bibliographical data

Original languageEnglish
Article number156
Publication statusPublished - 10.01.2022
Externally publishedYes

Comment Deanary

© 2022. The Author(s).

PubMed 35013174