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–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.