RESUMEN
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.
Asunto(s)
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Antígenos de Histocompatibilidad Clase I/genética , Neoplasias Pancreáticas/genética , Progranulinas/genética , Escape del Tumor/genética , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Animales , Anticuerpos Neutralizantes/farmacología , Antígenos Virales/genética , Antígenos Virales/inmunología , Autofagia/efectos de los fármacos , Autofagia/genética , Autofagia/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/terapia , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Estudios de Cohortes , Citotoxicidad Inmunológica , Expresión Génica , Glicoproteínas/genética , Glicoproteínas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Virus de la Coriomeningitis Linfocítica/genética , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Progranulinas/antagonistas & inhibidores , Progranulinas/inmunología , Proteolisis , Análisis de Supervivencia , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Proteínas Virales/genética , Proteínas Virales/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Synonymous mutations are generally disregarded by genomic analyses because they are considered non-pathogenic. We identified and characterized a somatic synonymous mutation in the epigenetic modifier and tumor suppressor BAP1, resulting in exon skipping and complete protein inactivation. This radically altered the prognosis of a clear-cell renal cell carcinoma patient from The Cancer Genome Atlas (TCGA) with a PBRM1 mutation (a predictor biomarker for positive responses to immune checkpoint inhibitors) from good (an estimated overall survival of 117 months) to a very bad prognosis (an estimated overall survival of 31 months), emphasizing the importance of scrutinizing synonymous mutations near acceptor splice sites of cancer genes for accurate precision medicine.
RESUMEN
Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based in vivo strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, whereas Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof of concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes.Significance: This study provides insight into the role of myeloid-dependent NOTCH signaling in PDAC and accentuates the need to dissect differential roles of signaling pathways in different cellular components within the tumor microenvironment. Cancer Res; 78(17); 4997-5010. ©2018 AACR.
