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
Bio- or muco-adhesive anchoring is a challenge for the development of advanced gastrointestinal (GI) surgical instruments, endoluminal monitoring devices and drug delivery systems. In this paper, we present a polymeric bio-adhesive film embedded with an optical sensor that can potentially be used to detect gastrointestinal bleeding. Four different formulas of mucoadhesive polymers were synthesized based on various chemical components and concentration combinations, and they were further layered with miniature photoplethymographic (PPG) sensors. The adhesive ability of the proposed mucoadhesive-sensor module was tested by attaching it to the lumen of a porcine stomach and compared amongst the four formulas. pH testing was also implemented to simulate the performance of the film in gastric cavity. To demonstrate the signal quality of this module, we also tested on the skin of five healthy subjects for hours. The observed shear detachment force between mucoadhesive film and porcine stomach tissue of all four formulations ranged from 0.09 to 1.38 N, and the performance of mucoadhesive film in pH 7 and pH 2 were similar. The module can attach firmly onto the skin for 3-10 hours with comparable PPG signal quality to traditional clip-based setup. With the advent of mucosal tissue anchoring by means of bioadhensive film, a wider extent of endoluminal procedures may become feasible. This emerging technology can also help shape the future of in-body wearable devices in the GI tract or other endoluminal cavities.
