journal contribution
posted on 2023-04-03, 22:46 authored by 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 Califano, Paul Robson, David A. Tuveson Supplementary Figure S1 shows the data quality and clustering metrics of the human PDAC single cell transcriptomes, Supplementary Figure S2 shows the distribution of sub-clusters of cells throughout the human dataset, Supplementary Figure S3 shows pathway analysis in human PDAC iCAFs and myCAFs, Supplementary Figure S4 shows the data quality and clustering metrics of the KPC mouse PDAC single cell transcriptomes, Supplementary Figure S5 shows pathway analysis in different KPC CAFs, Supplementary Figure S6 shows that Podoplanin is a pan-fibroblast marker in murine PDAC, Supplementary Figure S7 shows the validation of apCAFs in human PDAC, Supplementary Figure S8 shows the characterization of apCAFs in KPC and orthotopic transplantation models
Funding
Lustgarten Foundation
Cold Spring Harbor Laboratory Association
Thompson Foundation
Simons Foundation
National Institutes of Health
JAX Cancer Center
NCI
NIH
National Cancer Institute
Cold Spring Harbor Laboratory and Northwell Health Affiliation
History
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.
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
