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
High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.
