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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 156 (01 10 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35013174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Neutralizing
• Antigens, Viral
• GRN protein, human
• Glycoproteins
• Histocompatibility Antigens Class I
• Peptide Fragments
• Progranulins
• Viral Proteins
• glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus

Topics

• Adenocarcinoma (genetics, immunology, mortality, therapy)
• Animals
• Antibodies, Neutralizing (pharmacology)
• Antigens, Viral (genetics, immunology)
• Autophagy (drug effects, genetics, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology, pathology)
• Carcinoma, Pancreatic Ductal (genetics, immunology, mortality, therapy)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cohort Studies
• Cytotoxicity, Immunologic
• Gene Expression
• Glycoproteins (genetics, immunology)
• Histocompatibility Antigens Class I (genetics, immunology)
• Humans
• Lymphocytic choriomeningitis virus (genetics, immunology)
• Mice
• Pancreatic Neoplasms (genetics, immunology, mortality, therapy)
• Peptide Fragments (genetics, immunology)
• Progranulins (antagonists & inhibitors, genetics, immunology)
• Proteolysis
• Survival Analysis
• Tumor Escape (genetics)
• Tumor Microenvironment (genetics, immunology)
• Viral Proteins (genetics, immunology)
• Xenograft Model Antitumor Assays