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 language | English (US) |
|---|---|
| Pages (from-to) | 1102-1123 |
| Number of pages | 22 |
| Journal | Cancer discovery |
| Volume | 9 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2019 |
Fingerprint
ASJC Scopus subject areas
- Oncology
Cite this
Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. / Elyada, Ela; Bolisetty, Mohan; Laise, Pasquale; Flynn, William F.; Courtois, Elise T.; Burkhart, Richard; Teinor, Jonathan A.; Belleau, Pascal; Biffi, Giulia; Lucito, Matthew S.; Sivajothi, Santhosh; Armstrong, Todd D; Engle, Dannielle D.; Yu, Kenneth H.; Hao, Yuan; Wolfgang, Christopher; Park, Youngkyu; Preall, Jonathan; Jaffee, Elizabeth; Califano, Andrea; Robson, Paul; Tuveson, David A.
In: Cancer discovery, Vol. 9, No. 8, 01.08.2019, p. 1102-1123.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts
AU - Elyada, Ela
AU - Bolisetty, Mohan
AU - Laise, Pasquale
AU - Flynn, William F.
AU - Courtois, Elise T.
AU - Burkhart, Richard
AU - Teinor, Jonathan A.
AU - Belleau, Pascal
AU - Biffi, Giulia
AU - Lucito, Matthew S.
AU - Sivajothi, Santhosh
AU - Armstrong, Todd D
AU - Engle, Dannielle D.
AU - Yu, Kenneth H.
AU - Hao, Yuan
AU - Wolfgang, Christopher
AU - Park, Youngkyu
AU - Preall, Jonathan
AU - Jaffee, Elizabeth
AU - Califano, Andrea
AU - Robson, Paul
AU - Tuveson, David A.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070662203&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070662203&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-19-0094
DO - 10.1158/2159-8290.CD-19-0094
M3 - Review article
VL - 9
SP - 1102
EP - 1123
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 8
ER -