ERK Inhibition Improves Anti-PD-L1 Immune Checkpoint Blockade in Preclinical Pancreatic Ductal Adenocarcinoma

MOLECULAR CANCER THERAPEUTICS(2021)

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摘要
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-L1targeted PET tracer labeled with zirconium-89 (Zr-89). As theMAPK signaling pathway (MEK and ERK) is known to modulate PD-L1 expression in other tumor types, we used [Zr-89] Zr-DFO-anti-PDL1 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 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.
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