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.
Subject(s)
Adenocarcinoma/genetics , Carcinoma, Pancreatic Ductal/genetics , Histocompatibility Antigens Class I/genetics , Pancreatic Neoplasms/genetics , Progranulins/genetics , Tumor Escape/genetics , Adenocarcinoma/immunology , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Animals , Antibodies, Neutralizing/pharmacology , Antigens, Viral/genetics , Antigens, Viral/immunology , Autophagy/drug effects , Autophagy/genetics , Autophagy/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/therapy , Cell Line, Tumor , Cell Movement/drug effects , Cohort Studies , Cytotoxicity, Immunologic , Gene Expression , Glycoproteins/genetics , Glycoproteins/immunology , Histocompatibility Antigens Class I/immunology , Humans , Lymphocytic choriomeningitis virus/genetics , Lymphocytic choriomeningitis virus/immunology , Mice , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/therapy , Peptide Fragments/genetics , Peptide Fragments/immunology , Progranulins/antagonists & inhibitors , Progranulins/immunology , Proteolysis , Survival Analysis , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Viral Proteins/genetics , Viral Proteins/immunology , Xenograft Model Antitumor AssaysABSTRACT
TLR3 recognizes viral dsRNA and its synthetic mimetic polyinosinic-polycytidylic acid (poly(I:C)). TLR3 expression is commonly considered to be restricted to dendritic cells, NK cells, and fibroblasts. In this study we report that human gammadelta and alphabeta T lymphocytes also express TLR3, as shown by quantitative real-time PCR, flow cytometry, and confocal microscopy. Although T cells did not respond directly to poly(I:C), we observed a dramatic increase in IFN-gamma secretion and an up-regulation of CD69 when freshly isolated gammadelta T cells were stimulated via TCR in the presence of poly(I:C) without APC. IFN-gamma secretion was partially inhibited by anti-TLR3 Abs. In contrast, poly(I:C) did not costimulate IFN-gamma secretion by alphabeta T cells. These results indicate that TLR3 signaling is differentially regulated in TCR-stimulated gammadelta and alphabeta T cells, suggesting an early activation of gammadelta T cells in antiviral immunity.