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Cancer Discov. 2019 Aug;9(8):1102-1123. doi: 10.1158/2159-8290.CD-19-0094. Epub 2019 Jun 13.

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
2
Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.
3
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
4
Bristol-Myers Squibb, Pennington, New Jersey.
5
Department of Systems Biology, Columbia University Irving Medical Center, New York, New York.
6
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
7
Salk institute for Biological Studies, La Jolla, California.
8
Memorial Sloan Kettering Cancer Center, New York, New York.
9
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
10
J.P. Sulzberger Columbia Genome Center, Columbia University, New York, New York.
11
Department of Biomedical Informatics, Columbia University, New York, New York.
12
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York.
13
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut. dtuveson@cshl.edu paul.robson@jax.org.
14
Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut, Farmington, Connecticut.
15
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu paul.robson@jax.org.
#
Contributed equally

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.

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