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 |
|---|---|
| Pages (from-to) | 1102-1123 |
| Number of pages | 22 |
| Journal | Cancer Discovery |
| Volume | 9 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2019 |
| Externally published | Yes |
Bibliographical note
Funding Information:We would like to thank Hidde Ploegh for the MHCII–EGFP mice, Douglas Fearon and Ronald Evans for helpful insights and discussion, Arnaud Pommier, Naishitha Anaparthy, Morgan Truitt, Semir Beyaz, Michael Pickup, and Min Yao for their experiment suggestions and discussion, Richard Moffitt for his help with data analysis, Astrid Deschenes and Anthony Carcio for technical help, and Lindsey Baker and Tobiloba Oni for critical reading of the manuscript. This work was supported by the Lustgarten Foundation, where D.A. Tuveson is a distinguished scholar and Director of the Lustgarten Foundation Dedicated Laboratory of Pancreatic Cancer Research. D.A. Tuveson is also supported by the Cold Spring Harbor Laboratory Association, the David Rubinstein Center for Pancreatic Cancer Research at MSKCC, the V Foundation, the Thompson Foundation, and the Simons Foundation (552716). In addition, this work was supported by the National Institutes of Health, NIH P30CA045508, P50CA101955, P20CA192996, U10CA180944, U01CA168409, U01CA210240, R33CA206949, R01CA188134, and R01CA190092 to D.A. Tuveson and U01CA224013 to P. Robson and D.A. Tuveson. P. Robson is also supported by JAX laboratory startup funds and the JAX Cancer Center Support Grant (CCSG) P30CA034196-30. A. Califano is supported by the NCI Outstanding Investigator Award (R35 CA197745), the NCI Cancer Systems Biology Consortium (U54 CA209997), and two NIH Shared Instrumentation Grants (S10 OD012351, S10 OD0217640). A. Califano is also supported in part through the NCI Cancer Center Support Grant (P30 CA013696). E.M. Jaffee is supported by the James W. and Frances Gibson McGlothlin Foundation, the Skip Viragh Center for Pancreatic Cancer at Johns Hopkins, the Bloomberg–Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, the National Cancer Institute (R01 CA18492-04 and R01 CA19729603), and by a Stand Up To Cancer–Lustgarten Foundation Pancreatic Cancer Convergence Translational Research Grant (SU2C-AACR-DT14-14). C.L. Wolfgang is supported by the NIH (R01CA182076). R.A. Bur-khart is supported by a Stand Up To Cancer–Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research Grant (grant number SU2C-AACR-DT26-17). Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation administered by the American Association for Cancer Research, the Scientific Partner of SU2C. We also thank the Cold Spring Harbor Laboratory shared resources: P. Moody and C. Kanzler at the flow cytometry facility, C. Regan at the single-cell core, the animal facility, the histology core, the bioinformatics core, and the microscopy core. These shared resources are funded by the NIH Cancer Center Support Grant P30CA045508. In addition, we are grateful for support from the following: The Cold Spring Harbor Laboratory and Northwell Health Affiliation (for J. Preall and D.A. Tuveson), the Human Frontiers Science Program (LT000403/2014-L for E. Elyada and LT000195/2015-L for G. Biffi), EMBO (ALTF 1203-2014 for G. Biffi), NCI (R01 CA202762 for K.H. Yu, 5T32CA148056 and 5K99CA204725 for D.D. Engle), and the NIH (R50 CA211506-02 for Y. Park).
Funding Information:
We would like to thank Hidde Ploegh for the MHCII?EGFP mice, Douglas Fearon and Ronald Evans for helpful insights and discussion, Arnaud Pommier, Naishitha Anaparthy, Morgan Truitt, Semir Beyaz, Michael Pickup, and Min Yao for their experiment suggestions and discussion, Richard Moffitt for his help with data analysis, Astrid Deschenes and Anthony Carcio for technical help, and Lindsey Baker and Tobiloba Oni for critical reading of the manuscript. This work was supported by the Lustgarten Foundation, where D.A. Tuveson is a distinguished scholar and Director of the Lustgarten Foundation Dedicated Laboratory of Pancreatic Cancer Research. D.A. Tuveson is also supported by the Cold Spring Harbor Laboratory Association, the David Rubinstein Center for Pancreatic Cancer Research at MSKCC, the V Foundation, the Thompson Foundation, and the Simons Foundation (552716). In addition, this work was supported by the National Institutes of Health, NIH P30CA045508, P50CA101955, P20CA192996, U10CA180944, U01CA168409, U01CA210240, R33CA206949, R01CA188134, and R01CA190092 to D.A. Tuveson and U01CA224013 to P. Robson and D.A. Tuveson. P. Robson is also supported by JAX laboratory startup funds and the JAX Cancer Center Support Grant (CCSG) P30CA034196-30. A. Califano is supported by the NCI Outstanding Investigator Award (R35 CA197745), the NCI Cancer Systems Biology Consortium (U54 CA209997), and two NIH Shared Instrumentation Grants (S10 OD012351, S10 OD0217640). A. Califano is also supported in part through the NCI Cancer Center Support Grant (P30 CA013696). E.M. Jaffee is supported by the James W. and Frances Gibson McGlothlin Foundation, the Skip Viragh Center for Pancreatic Cancer at Johns Hopkins, the Bloomberg?Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, the National Cancer Institute (R01 CA18492-04 and R01 CA19729603), and by a Stand Up To Cancer?Lustgarten Foundation Pancreatic Cancer Convergence Translational Research Grant (SU2C-AACR-DT14-14). C.L. Wolfgang is supported by the NIH (R01CA182076). R.A. Burkhart is supported by a Stand Up To Cancer?Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research Grant (grant number SU2C-AACR-DT26-17). Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation administered by the American Association for Cancer Research, the Scientific Partner of SU2C. We also thank the Cold Spring Harbor Laboratory shared resources: P. Moody and C. Kanzler at the flow cytometry facility, C. Regan at the single-cell core, the animal facility, the histology core, the bioinformatics core, and the microscopy core. These shared resources are funded by the NIH Cancer Center Support Grant P30CA045508. In addition, we are grateful for support from the following: The Cold Spring Harbor Laboratory and Northwell Health Affiliation (for J. Preall and D.A. Tuveson), the Human Frontiers Science Program (LT000403/2014-L for E. Elyada and LT000195/2015-L for G. Biffi), EMBO (ALTF 1203-2014 for G. Biffi), NCI (R01 CA202762 for K.H. Yu, 5T32CA148056 and 5K99CA204725 for D.D. Engle), and the NIH (R50 CA211506-02 for Y. Park).
Publisher Copyright:
© 2019 American Association for Cancer Research.
