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.
Highlights
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
We found that mRNA expression of NT5E, TGFB1, FN1, and ITGA5 is enriched in aggressive subtype of PDA (Figs 3e,f, S5a,c,e,g,i,j), and that PDA having high expression of those genes showed poor prognosis in the International Cancer Genome Consortium (ICGC) and/or in the TGCA cohorts (Figs 3g, S5b,d,f,h,k)
Recent studies conducted in Genetically engineered mouse models (GEMMs) have demonstrated that the selective targeting of myeloid cell populations influence gene expression programs of cancer cells[11,12]
Summary
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. 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. Based on intrinsic characteristics of neoplastic cells, PDA can be reliably classified as Squamous/Basal-like or Classical/Pancreatic Progenitor, whereas ADEX and Immunogenic subtype appear to be driven by transcripts from non-neoplastic cells[8] These tumour subtypes show different prognosis and different response to therapy[7,9]. Engineered mouse models (GEMMs) of PDA have demonstrated to faithfully recapitulate major pathophysiological features of the human disease, including the prominent stromal reaction that involves immune cells[15,16]. We characterized the cellular components and the dynamic changes of the immune contexture during progression of pancreatic tumour organoid derived isografts
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