Journal
CANCER DISCOVERY
Volume 9, Issue 8, Pages 1102-1123Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-0094
Keywords
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Categories
Funding
- Lustgarten Foundation
- Cold Spring Harbor Laboratory Association
- David Rubinstein Center for Pancreatic Cancer Research at MSKCC
- V Foundation
- Thompson Foundation
- Simons Foundation [552716]
- National Institutes of Health, NIH [P30CA045508, P50CA101955, P20CA192996, U10CA180944, U01CA168409, U01CA210240, R33CA206949, R01CA188134, R01CA190092, U01CA224013]
- JAX laboratory startup funds
- JAX Cancer Center Support Grant (CCSG) [P30CA034196-30]
- NCI Outstanding Investigator Award [R35 CA197745]
- NCI Cancer Systems Biology Consortium [U54 CA209997]
- NIH Shared Instrumentation Grants [S10 OD012351, S10 OD0217640]
- NCI Cancer Center Support Grant [P30 CA013696]
- James W. and Frances Gibson McGlothlin Foundation
- Skip Viragh Center for Pancreatic Cancer at Johns Hopkins
- National Cancer Institute [R01 CA18492-04, R01 CA19729603]
- Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Translational Research Grant [SU2C-AACR-DT14-14]
- NIH [R01CA182076, R50 CA211506-02]
- Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research Grant [SU2C-AACR-DT26-17]
- NIH Cancer Center Support Grant [P30CA045508]
- The Cold Spring Harbor Laboratory and Northwell Health Affiliation
- Human Frontiers Science Program [LT000403/2014-L, LT000195/2015-L]
- EMBO [ALTF 1203-2014]
- NCI [R01 CA202762, 5T32CA148056, 5K99CA204725]
- Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
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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.
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