Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts

Ela Elyada, Mohan Bolisetty, Pasquale Laise, William F. Flynn, Elise T. Courtois, Richard A. Burkhart, Jonathan A. Teinor, Pascal Belleau, Giulia Biffi, Matthew S. Lucito, Santhosh Sivajothi, Todd D. Armstrong, Dannielle D. Engle, Kenneth H. Yu, Yuan Hao, Christopher L. Wolfgang, Youngkyu Park, Jonathan Preall, Elizabeth M. Jaffee, Andrea CalifanoPaul Robson, David A. Tuveson

Research output: Contribution to journalReview article

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.

Original languageEnglish (US)
Pages (from-to)1102-1123
Number of pages22
JournalCancer discovery
Volume9
Issue number8
DOIs
StatePublished - Aug 2019

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ASJC Scopus subject areas

  • Oncology

Cite this

Elyada, E., Bolisetty, M., Laise, P., Flynn, W. F., Courtois, E. T., Burkhart, R. A., Teinor, J. A., Belleau, P., Biffi, G., Lucito, M. S., Sivajothi, S., Armstrong, T. D., Engle, D. D., Yu, K. H., Hao, Y., Wolfgang, C. L., Park, Y., Preall, J., Jaffee, E. M., ... Tuveson, D. A. (2019). Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer discovery, 9(8), 1102-1123. https://doi.org/10.1158/2159-8290.CD-19-0094