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Published on: September 25, 2018
Photochemical enhancement of PD-L1-SAP immunotoxin efficacy in non-small cell lung cancer cell lines
Magdaléna Kozlíková1,2, Inger Kristine Fjeldskaar Aukrust2, Monika Rohlíčková1
1Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czechia.
Introduction:
Resistance to immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis remains a major obstacle in non-small cell lung cancer (NSCLC).
Materials And Methods:
To address this, we investigated photochemical internalization (PCI), a light-controlled endosomal escape technology, as a strategy to enhance intracellular delivery and efficacy of a PD-L1-targeted immunotoxin (anti-PD-L1-SAP).
Results:
NSCLC cell lines with high (NCI-H1975) and low (A549) PD-L1 expression were subjected to PCI, resulting in a pronounced increase in cytotoxicity with picomolar potency (30 pM), while A549 cells required a higher dose (1000 pM) for a similar effect. Specificity was confirmed via receptor blockade and non-targeted controls. Confocal microscopy demonstrated lysosomal and endosomal localization of anti-PD-L1-SAP, and flow cytometry showed time-dependent intracellular accumulation, consistent with PCI's requirement for endosomal sequestration prior to light-induced release. Importantly, co-treatment with the immune checkpoint inhibitor atezolizumab (Tecentriq®) reduced PCI efficacy in PD-L1^high^ cells, underscoring the importance of receptor accessibility.
Conclusions:
These findings demonstrate that PCI enhances delivery and activity of PD-L1-targeted biologics and may help overcome resistance mechanisms. Overall, PCI expands the therapeutic window of PD-L1-targeted immunotoxins and may complement current immunotherapies, supporting further preclinical evaluation in NSCLC.
Insights
Photochemical internalization (PCI) enhances the delivery and effectiveness of PD-L1-targeted immunotoxins for non-small cell lung cancer (NSCLC). This light-controlled technology may help overcome resistance to current immunotherapies.
Area of Science:
- Oncology
- Immunotherapy
- Drug Delivery
Background:
- Resistance to immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis is a significant challenge in non-small cell lung cancer (NSCLC).
- Novel strategies are needed to improve the efficacy of PD-L1-targeted therapies.
Purpose of the Study:
- To investigate photochemical internalization (PCI) as a method to enhance the intracellular delivery and efficacy of a PD-L1-targeted immunotoxin (anti-PD-L1-SAP).
- To assess the potential of PCI to overcome resistance mechanisms in NSCLC.
Main Methods:
- Utilized NSCLC cell lines with varying PD-L1 expression (high: NCI-H1975, low: A549).
- Applied photochemical internalization (PCI) to enhance delivery of anti-PD-L1-SAP.
- Confirmed specificity using receptor blockade and non-targeted controls.
- Analyzed intracellular localization and accumulation via confocal microscopy and flow cytometry.
Main Results:
- PCI significantly increased the cytotoxicity of anti-PD-L1-SAP in NSCLC cells, achieving picomolar potency.
- High PD-L1 expressing cells showed greater sensitivity to PCI-enhanced treatment.
- Confocal microscopy and flow cytometry confirmed PCI's mechanism of endosomal escape and intracellular delivery.
- Concurrent treatment with atezolizumab reduced PCI efficacy, highlighting the importance of receptor accessibility.
Conclusions:
- PCI effectively enhances the delivery and activity of PD-L1-targeted biologics, including immunotoxins.
- PCI demonstrates potential to overcome resistance to PD-L1-targeted therapies in NSCLC.
- PCI may broaden the therapeutic window for PD-L1 immunotoxins and complement existing immunotherapies, warranting further preclinical investigation.
