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Cross-species Single Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-presenting Cancer-associated Fibroblasts

ABSTRACT: Cross-species Single Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-presenting Cancer-associated Fibroblasts

PROVIDER: PRJNA547653 | ENA |

REPOSITORIES: ENA

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Cross-species Single Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-presenting Cancer-associated Fibroblasts

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Project description:Cancer-associated fibroblasts (CAF) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we use single-cell RNA sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human and mouse PDAC tumors. We corroborate the presence of myofibroblastic CAFs and inflammatory CAFs and define their unique gene signatures in vivo. Moreover, we describe a new population of CAFs that express MHC class II and CD74, but do not express classic costimulatory molecules. We term this cell population "antigen-presenting CAFs" and find that they activate CD4+ T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Our cross-species analysis paves the way for investigating distinct functions of CAF subtypes in PDAC immunity and progression. SIGNIFICANCE: Appreciating the full spectrum of fibroblast heterogeneity in pancreatic ductal adenocarcinoma is crucial to developing therapies that specifically target tumor-promoting CAFs. This work identifies MHC class II-expressing CAFs with a capacity to present antigens to CD4+ T cells, and potentially to modulate the immune response in pancreatic tumors.See related commentary by Belle and DeNardo, p. 1001.This article is highlighted in the In This Issue feature, p. 983.

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RNA-seq expression profiling of ductal macrophages and antigen presenting cells from virgin mouse mammary glands

Project description:Macrophages are diverse immune cells that reside in all tissues to regulate development, function and homeostasis. In the mammary gland, a highly dynamic organ that undergoes dramatic remodeling throughout life, macrophages have been implicated in development and breast tumorigenesis. Ductal macrophages, as opposed to their stromal counterparts, were found to promote ductal morphogenesis during puberty and efficiently phagocytose alveolar cells post-lactation. Within mammary tumors, only ductal macrophages expanded to form a network throughout the tumor, where they also contact intra-tumoral T cells. Furthermore, ductal macrophages accelerated the growth of tumor organoids. Thus, pro-remodeling mammary ductal macrophages represent the normal tissue counterpart of tumor macrophages in an organ that is highly susceptible to oncogenesis. To gain insight into ductal macrophage function, we sorted all antigen presenting cell populations from mouse mammary glands and undertook RNA-seq expression profiling. This showed that ductal macrophages have a distinct expression profile from those of stromal macrophages or dendritic cells from the mammary gland. Results from this data series are presented in Figure 2 of Dawson et al (2020).

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