RESUMO
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.
Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Antígenos de Histocompatibilidade Classe I/genética , Neoplasias Pancreáticas/genética , Progranulinas/genética , Evasão Tumoral/genética , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Animais , Anticorpos Neutralizantes/farmacologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Autofagia/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Estudos de Coortes , Citotoxicidade Imunológica , Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Vírus da Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Progranulinas/antagonistas & inibidores , Progranulinas/imunologia , Proteólise , Análise de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
