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

Ela Elyada
Mohan Bolisetty
Pasquale Laise
William F Flynn, The Jackson Laboratory
Elise T Courtois, The Jackson Laboratory
Richard A Burkhart
Jonathan A Teinor
Pascal Belleau
Giulia Biffi
Matthew S Lucito
Santhosh Sivajothi, The Jackson Laboratory
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, The Jackson Laboratory
David A Tuveson


Cancer-associated fibroblasts (CAFs) 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 employ 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 (myCAFs) and inflammatory CAFs (iCAFs) 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 classical co-stimulatory molecules. We term this cell population "antigen-presenting CAFs" (apCAFs), 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.