Author ORCID Identifier
0000-0002-4900-1560
Date of Graduation
8-2023
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Florencia McAllister, M.D
Committee Member
Guillermina Lozano, Ph.D.
Committee Member
Laura Bover, Ph.D.
Committee Member
Seyed Javad Moghaddam, M.D
Committee Member
Anirban Maitra, M.B.B.S..
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths. PDAC is characterized by the early establishment of a highly immunosuppressive fibro-cellular tumor microenvironment (TME). Our research has revealed the important role of IL-17 in the development and progression of pancreatic cancer, yet the specific cellular compartment responsible for IL-17-mediated tumor promotion remains unknown. We generated a transgenic mouse model with pancreatic KrasG12D activation and selective deletion of IL-17RA in the epithelial vs. immune component using either genetic manipulation or bone marrow transplantation. Deletion of IL17RA from the pancreatic epithelial compartment delayed premalignant lesion development and resulted in increased tumor infiltration of cytotoxic CD8+ T cells. We used single-cell sequencing to gain insight into the transcriptional changes induced by the absence of IL-17RA in the pancreatic compartment. From the epithelial global analysis, regulation of B7-H4 emerged as one of the main immune-related pathways driven by IL17A. B7-H4 is a negative regulator of T cells through Eomes activation. To further investigate the significance of B7-H4 during tumorigenesis, we generated transgenic mice lacking B7-H4 expression. Transgenic animals with pancreatic KrasG12D activation with global deletion of B7-H4 exhibited delayed tumorigenesis and reduced immunosuppression, emphasizing the role of IL-17-driven B7-H4 in tumor development and immune modulation. Moreover, we generated pharmacological and genetic tools to inhibit B7-H4 and tested them in different animal models. The results showed vii that B7-H4 may play a role in PDAC development. In summary, we determined that the pancreatic epithelial compartment is required for IL17-driven tumorigenesis which effect is at least partially mediated by B7-H4.
Keywords
Pancreatic Cancer, IL-17, B7-H4, mouse models