Frontiers in immunology · 2026
Photochemical enhancement of PD-L1-SAP immunotoxin efficacy in non-small cell lung cancer cell lines.
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Kozlíková Magdaléna, Aukrust Inger Kristine Fjeldskaar, Rohlíčková Monika, Macháček Miloslav, Berg Kristian, Weyergang Anette, Selbo Pål Kristian
Аннотация
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.
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.