Author ORCID Identifier
Date Available
8-2-2022
Year of Publication
2022
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Clinical and Translational Science
First Advisor
Dr. Joseph Kim
Second Advisor
Dr. Thomas H. Kelly
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with few treatment options, necessitating an urgent need for novel therapeutics. Immuno-oncologic (IO) therapies have revolutionized anti-cancer regimens in the past decade but typically involve reactivation of adaptive immune responses. In particular, immune checkpoint PD-1 is traditionally expressed only on immune cells while PD-L1 (PD-1 ligand) is overexpressed on cancer cells. When tumor-endogenous PD-L1 binds the PD-1 receptor on T-cells, the immune cells undergo anergy resulting in self-tolerance and cancer cell immune evasion. However, contrary to standard dogma, we previously demonstrated tumor-endogenous PD-1 expression in PDAC. Our data indicated that PD-1 proteins are not exclusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we aimed to further characterize PD-1 expression in PDAC.
Here, we demonstrate that tumor-endogenous PD-1 unexpectedly regulates downstream oncogenic pathways in PDAC. However, unlike PD-1 activation in immune cells leading to apoptosis, we found that tumor-endogenous PD-1 signaling instead increased cancer cell growth, proliferation, and migration by regulating the proto-oncogene MET. This process was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a hallmark of oncogenic transformation in PDAC. We next observed that combined therapeutic targeting of PDAC cell PD-1 and MET resulted in substantial direct tumor cell cytotoxicity and growth inhibition in PDAC cell lines, patient-derived organoids, and patient-derived xenografts independent of immune cytotoxic responses. These responses represent a form of previously undescribed oncogene addiction depicting tumor-endogenous PD-1 as an unrecognized proto-oncogene.
Altogether, we demonstrated that the traditionally immune-specific PD-1 has a non-immunogenic phenotype when expressed on PDAC cells, resulting in activation of oncogenic processes that can be targeted by therapeutic regimens to enable direct tumor cytotoxicity. This is the first report of a PD-1/MET interaction, PD-1 induction of EMT, or PD-1 functioning as a proto-oncogene in any cancer. Given the urgent need for new PDAC therapeutics, our novel mechanism presents a prime target for direct and indirect therapeutic antagonism in PDAC.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2022.262
Funding Information
This research was supported by the National Institutes of Health Training Grant T32CA160003 (2020-2022, M.M.H.).
Recommended Citation
Harper, Megan M., "NOVEL MECHANISM OF ENDOGENOUS PANCREATIC CANCER CELL EXPRESSION OF IMMUNE CHECKPOINT PROGRAMMED CELL-DEATH 1 PROTEIN (PD-1) INDUCING EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) THROUGH THE MET PATHWAY AND PROMOTING CANCER PROGRESSION IN AN IMMUNE-INDEPENDENT PROCESS" (2022). Theses and Dissertations--Clinical and Translational Science. 17.
https://uknowledge.uky.edu/cts_etds/17
