Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts

Abstract

Abstract 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

Keywords

Affiliated Institutions

• Columbia University US
• Columbia University Irving Medical Center US
• Sidney Kimmel Comprehensive Cancer Center US
• Salk Institute for Biological Studies US
• Lustgarten Foundation US
• Jackson Laboratory US
• Bristol-Myers Squibb (United States) US
• Johns Hopkins University US
• University of Connecticut US
• Cold Spring Harbor Laboratory US
• Kettering University US
• Memorial Sloan Kettering Cancer Center US

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