A new study has revealed an underlying mechanism involved in PD-L1 regulation by ERK signaling that induces autophagy in intrahepatic cholangiocarcinoma (iCCA).
The study, published in Cancer Cell International, reports distinctly reduced PD-L1 expression in KRAS-mutated iCCA cell lines via ERK signaling inhibition, suggesting ERK-targeted therapy might represent a novel immune-related approach to treatment for iCCA.
“The present study elucidated a novel mechanism by which ERK signaling regulates the PD-L1 expression via the autophagy degradation pathway and enhances the T cell-mediated immune response,” the authors wrote. “These findings shed light on the clinical application of ERK-targeted therapy together with anti-PD-1/PD-L1 immunotherapy, which represents a promising strategy for [KRAS]-mutated iCCA treatment.”
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KRAS mutations are known oncogenic drivers in CCA, but studies specifically on the effect of ERK inhibitors on PD-L1 expression have been lacking. Based on recent studies showing that PD-L1 expression is stimulated via the ERK signaling pathway, the research team postulated that inhibition of ERK would have the opposite effect.
After treatment with ERK signaling inhibitors such as SCH772984 (ERK1/2), immunofluorescent staining analyses confirmed a reduced expression of PD-L1 in human iCCA cell lines, indicating that KRAS-mutated iCCA cells do in fact induce PD-L1 expression via the ERK signaling pathway.
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Furthermore, additional reports have indicated that inhibition of ERK signaling can lead to autophagy, which might be implicated in the reduction of PD-L1 expression. After treating iCCA cells with ERK1/2 inhibitor, the researchers observed autophagy induction concurrently with reduced PD-L1 expression. Thus, autophagy appears to be a component of the mechanism underlying intracellular reductions in PD-L1.
A new study has revealed an underlying mechanism involved in PD-L1 regulation by ERK signaling that induces autophagy in intrahepatic cholangiocarcinoma (iCCA).
The study, published in Cancer Cell International, reports distinctly reduced PD-L1 expression in KRAS-mutated iCCA cell lines via ERK signaling inhibition, suggesting ERK-targeted therapy might represent a novel immune-related approach to treatment for iCCA.
The research team expects these results will contribute to novel clinical applications of ERK-targeted therapy which, when combined with anti-PD-L1 immunotherapy, might represent a promising approach for patients with KRAS-mutated iCCA.
Reference
Gao Z., Chen JF, Li XG. et al. KRAS acting through ERK signaling stabilizes PD-L1 via inhibiting autophagy pathway in intrahepatic cholangiocarcinoma. Cancer Cell Int. Published online March 19, 2022. doi:10.1186/s12935-022-02550-w
