Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest forms of cancer, in part, because it is largely refractory to current therapies. The failure of most standard therapies in PDA, as well as promising immune therapies, may be largely ascribed to highly unique and protective stromal microenvironments that present significant biophysical barriers to effective drug delivery, that are immunosuppressive, and that can limit the distribution and function of antitumor immune cells. Here, we utilized stromal reengineering to disrupt these barriers and move the stroma toward normalization using a potent antifibrotic agent, halofuginone. In an autochthonous genetically engineered mouse model of PDA, halofuginone disrupted physical barriers to effective drug distribution by decreasing fibroblast activation and reducing key extracellular matrix elements that drive stromal resistance. Concomitantly, halofuginone treatment altered the immune landscape in PDA, with greater immune infiltrate into regions of low hylauronan, which resulted in increased number and distribution of both classically activated inflammatory macrophages and cytotoxic T cells. In concert with a direct effect on carcinoma cells, this led to widespread intratumoral necrosis and reduced tumor volume. These data point to the multifunctional and critical role of the stroma in tumor protection and survival and demonstrate how compromising tumor integrity to move toward a more normal physiologic state through stroma-targeting therapy will likely be an instrumental component in treating PDA. SIGNIFICANCE: This work demonstrates how focused stromal re-engineering approaches to move toward normalization of the stroma disrupt physical barriers to effective drug delivery and promote antitumor immunity. See related commentary by Huang and Brekken, p. 328.
Bibliographical noteFunding Information:
P.P. Provenzano and this work was supported by the NIH (R01CA181385 and U54CA210190 University of Minnesota Physical Sciences in Oncology Center to P.P. Provenzano and a SPORE Development award under P50CA101955 to P.P. Provenzano) and by a Research Scholar Grant, RSG-14-171-01-CSM from the American Cancer Society (to P.P. Provenzano). This work was also supported by the Randy Shaver Research and Community Fund, UMN College of Science and Engineering, Masonic Cancer Center, and grants from the UMN Institute for Engineering in Medicine (all to P.P. Provenzano). K. Elahi-Gedwillo received support from the Department of Education (GAANN fellowship through grant #P200A120198) and ARCS (Achievement Rewards for College Scientists Foundation, Inc.). The authors thank Courtney Podritz and Ben Cooper for their assistance with pilot experiments. We would also like to thank Dr. Ajay Dixit for isolating the human-derived primary PSCs used in our in vitro studies and members of the Provenzano laboratory for insightful comments regarding this work.
© 2018 American Association for Cancer Research.
- Biophysical Phenomena
- CD8-Positive T-Lymphocytes/drug effects
- Carcinoma, Pancreatic Ductal/drug therapy
- Cell Line, Tumor
- Doxorubicin/administration & dosage
- Drug Delivery Systems
- Macrophages/drug effects
- Pancreatic Neoplasms/drug therapy
- Random Allocation
- Stromal Cells/drug effects
- Tumor Microenvironment/drug effects
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Journal Article
- Research Support, N.I.H., Extramural