Immunoevolution of mouse pancreatic organoid isografts from preinvasive to metastatic disease.
Sci Rep
; 9(1): 12286, 2019 08 22.
Article
en En
| MEDLINE
| ID: mdl-31439856
ABSTRACT
Pancreatic ductal adenocarcinoma (PDA) has a highly immunosuppressive microenvironment, which is contributed by the complex interaction between cancer cells and a heterogeneous population of stromal cells. Therefore, facile and trackable models are needed for integrative and dynamic interrogation of cancer-stroma interaction. Here, we tracked the immunoevolution of PDA in a genetically-defined transplantable model of mouse pancreatic tumour organoids that recapitulates the progression of the disease from early preinvasive lesions to metastatic carcinomas. We demonstrated that organoid-derived isografts (ODI) can be used as a biological source of biomarkers (NT5E, TGFB1, FN1, and ITGA5) of aggressive molecular subtypes of human PDA. In ODI, infiltration from leukocytes is an early event during progression of the disease as observed for autochthonous models. Neoplastic progression was associated to accumulation of Maf+ macrophages, which inversely correlated with CD8+ T cells infiltration. Consistently, levels of MAF were enriched in human PDA subtypes characterized by abundance of macrophage-related transcripts and indicated poor patients' survival. Density of MAF+ macrophages was higher in human PDA tissues compared to preinvasive lesions. Our results suggest that ODIs represent a suitable system for genotypic-immunophenotypic studies and support the hypothesis of MAF+ macrophages as a prominent immunosuppressive population in PDA.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Linfocitos T CD8-positivos
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Carcinoma Ductal Pancreático
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Microambiente Tumoral
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Macrófagos
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Sci Rep
Año:
2019
Tipo del documento:
Article
País de afiliación:
Italia