Abstract
We recently demonstrated that immune checkpoint PD-1 was endogenously expressed in pancreatic ductal adenocarcinoma (PDAC) cells. Our data indicated that PD-1 proteins are not ex-clusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we sought to further characterize PD-1 expression in PDAC. We utilized a phospho-explorer array to identify pathways upregulated by PD-1 signaling. We discovered PD-1-mediated activation of the proto-oncogene MET in PDAC cells, which was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. We then discovered that the PD-1/MET axis in PDAC cells regulated growth, migration, and invasion. Im-portantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-estab-lished early oncogenic process in PDAC. We observed that combined 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 cytotoxic immune responses. This is the first report of PDAC-endogenous PD-1 expression regulating MET signaling, which builds upon our growing body of work showing the oncogenic phenotype of PD-1 expression in PDAC cells is distinct from its immunogenic role. These results highlight a paradigm shift that the tumor-specific PD-1 axis is a novel target to effectively kill PDAC cells by antagonizing previously unrecognized PD-1-dependent oncogenic pathways.
Original language | English |
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Article number | 3051 |
Journal | Cancers |
Volume | 14 |
Issue number | 13 |
DOIs | |
State | Published - Jul 1 2022 |
Bibliographical note
Funding Information:Funding: This research was supported by the Biospecimen Procurement and Translational Pathology (BPTP) Shared Resource Facility (SRF) of the University of Kentucky (UK), Markey Cancer Center (NIH P30CA177558), and NIH training grant T32CA160003 (M.M.H.).
Funding Information:
Conflicts of Interest: J.K. received funding from Merck and Exelixis to conduct clinical trial NCT05052723. No financial support was received from Merck or Exelixis for any of the current research studies. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The remaining authors declare no potential conflicts of interest.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- epithelial-mesenchy-mal transition
- immune checkpoint inhibitors
- pancreatic neoplasm
- programmed cell death 1 receptor
- proto-oncogene protein c-met
ASJC Scopus subject areas
- Oncology
- Cancer Research