ERK inhibition improves anti-PD-L1 immune checkpoint blockade in preclinical pancreatic ductal adenocarcinoma Journal Article
| Authors: | Henry, K. E.; Mack, K. N.; Nagle, V. L.; Cornejo, M.; Michel, A. O.; Fox, I. L.; Davydova, M.; Dilling, T. R.; Pillarsetty, N.; Lewis, J. S. |
| Article Title: | ERK inhibition improves anti-PD-L1 immune checkpoint blockade in preclinical pancreatic ductal adenocarcinoma |
| Abstract: | 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–PDL1 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 CD8þ 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. ©2021 American Association for Cancer Research |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 20 |
| Issue: | 10 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-10-01 |
| Start Page: | 2026 |
| End Page: | 2034 |
| Language: | English |
| DOI: | 10.1158/1535-7163.Mct-20-1112 |
| PUBMED: | 34349003 |
| PROVIDER: | scopus |
| PMCID: | PMC8492510 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2021 -- Source: Scopus |
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