ERK Inhibition Improves Anti-PD-L1 Immune Checkpoint Blockade in Preclinical Pancreatic Ductal Adenocarcinoma
| Autor: | Mike Cornejo, Jason S. Lewis, Ian L. Fox, Thomas R. Dilling, Adam O. Michel, Kelly E. Henry, Nagavarakishore Pillarsetty, Maria Davydova, Veronica L. Nagle, Kyeara N. Mack |
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| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
Male Cancer Research Pancreatic ductal adenocarcinoma medicine.medical_treatment Apoptosis B7-H1 Antigen Article Targeted therapy Mice Tumor Cells Cultured Medicine Animals Humans Extracellular Signal-Regulated MAP Kinases Immune Checkpoint Inhibitors Protein Kinase Inhibitors Cell Proliferation business.industry Drug Synergism Xenograft Model Antitumor Assays Immune checkpoint Blockade Clinical trial Gene Expression Regulation Neoplastic Mice Inbred C57BL Pancreatic Neoplasms Oncology Cancer research Immunohistochemistry Drug Therapy Combination business CD8 Carcinoma Pancreatic Ductal |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 |
| Popis: | Patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint blockade (ICB) along the PD-1/PD-L1 axis. Variable PD-L1 expression in PDAC indicates a potential access issue of PD-L1–targeted therapy. To monitor target engagement of PD-L1–targeted therapy, we generated a PD-L1–targeted PET tracer labeled with zirconium-89 (89Zr). As the MAPK signaling pathway (MEK and ERK) is known to modulate PD-L1 expression in other tumor types, we used [89Zr]Zr-DFO-anti–PD-L1 as a tool to noninvasively assess whether manipulation of the MAPK signaling cascade could be leveraged to modulate PD-L1 expression and thereby immunotherapeutic outcomes in PDAC. In this study, we observed that the inhibition of MEK or ERK is sufficient to increase PD-L1 expression, which we hypothesized could be leveraged for anti–PD-L1 immune checkpoint therapy. We found that the combination of ERK inhibition and anti–PD-L1 therapy corresponded with a significant improvement of overall survival in a syngeneic mouse model of PDAC. Furthermore, IHC analysis indicates that the survival benefit may be CD8+ T-cell mediated. The therapeutic and molecular imaging tool kit developed could be exploited to better structure clinical trials and address the therapeutic gaps in challenging malignancies such as PDAC. |
| Databáze: | OpenAIRE |
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