WCLC 2025 - Posters & ePosters-P2.02.12 hUC-MSC-Derived Exosomes Mitigates Immune Checkpoint Inhibitor-Associated Lung Injury by Suppressing GSDME-Mediated Pyroptosis

P2.02.12 hUC-MSC-Derived Exosomes Mitigates Immune Checkpoint Inhibitor-Associated Lung Injury by Suppressing GSDME-Mediated Pyroptosis

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This study investigates the therapeutic potential of human umbilical cord-derived mesenchymal stem cell exosomes (hUC-MSC-exos) in mitigating immune checkpoint inhibitor-associated lung injury (ICI-LI), a serious adverse effect seen in 3-18.5% of patients treated with ICIs targeting PD-1/PD-L1 or CTLA-4. ICI-LI is partly driven by pyroptosis, a form of programmed inflammatory cell death mediated by the CASPASE3/GSDME pathway. Current treatments like glucocorticoids are often insufficient, highlighting the need for novel therapies.<br /><br />Researchers isolated and characterized hUC-MSC-exos and tested their effects in ICI-LI mouse models and pyroptosis-induced human bronchial epithelial (HBE) cells. They found that hUC-MSC-exos significantly alleviated lung injury and suppressed GSDME-mediated pyroptosis both in vivo and in vitro. Small RNA sequencing revealed that miR-21-5p was highly enriched in these exosomes. Functional analyses showed that miR-21-5p targets the APAF1 gene, leading to inhibition of the APAF1/CASPASE3/GSDME/IL1β signaling axis responsible for pyroptosis.<br /><br />Administration of miR-21-5p mimics or agomirs validated the mechanism whereby exosomal miR-21-5p reduces lung injury and inflammatory cell death by blocking APAF1 expression, thereby preventing CASPASE3 activation and subsequent GSDME cleavage. This mechanistic insight is illustrated schematically and supported by rigorous experimental data.<br /><br />The study concludes that hUC-MSC-exos hold promise as a novel treatment strategy for ICI-LI through suppression of GSDME-mediated pyroptosis. Future research directions include further clinical evaluation of these exosomes as targeted therapies to mitigate immune-related lung injury in cancer patients receiving ICIs. This work provides a compelling foundation for using stem cell-derived exosomal miRNAs to modulate pathological cell death pathways in inflammatory lung diseases.

Asset Subtitle

Zekun Chenli

Meta Tag

Speaker Zekun Chenli

Topic Tumor Biology – Preclinical Biology

Keywords

human umbilical cord-derived mesenchymal stem cell exosomes

hUC-MSC-exos

immune checkpoint inhibitor-associated lung injury

ICI-LI

pyroptosis

CASPASE3/GSDME pathway

miR-21-5p

APAF1 gene

immune checkpoint inhibitors

inflammatory lung diseases