Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35013174.
- Also identified by DOI 10.1038/s41467-021-27088-9 and PMC identifier 8748938.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>+</sup> 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.
Medical subject headings
- Adenocarcinoma
- Carcinoma, Pancreatic Ductal
- Histocompatibility Antigens Class I
- Pancreatic Neoplasms
- Progranulins
- Tumor Escape