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Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells

Human cytotoxic T lymphocytes (CTLs) exhibit ultrarapid lytic granule secretion, but whether melanoma cells mobilize defense mechanisms with commensurate rapidity remains unknown. We used single-cell time-lapse microscopy to offer high spatiotemporal resolution analyses of subcellular events in mela...

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Detalles Bibliográficos
Autores principales: Filali, Liza, Puissegur, Marie-Pierre, Cortacero, Kevin, Cussat-Blanc, Sylvain, Khazen, Roxana, Van Acker, Nathalie, Frenois, François-Xavier, Abreu, Arnaud, Lamant, Laurence, Meyer, Nicolas, Vergier, Béatrice, Müller, Sabina, McKenzie, Brienne, Valitutti, Salvatore
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849291/
https://www.ncbi.nlm.nih.gov/pubmed/35171665
http://dx.doi.org/10.1126/sciadv.abk3234
Descripción
Sumario:Human cytotoxic T lymphocytes (CTLs) exhibit ultrarapid lytic granule secretion, but whether melanoma cells mobilize defense mechanisms with commensurate rapidity remains unknown. We used single-cell time-lapse microscopy to offer high spatiotemporal resolution analyses of subcellular events in melanoma cells upon CTL attack. Target cell perforation initiated an intracellular Ca(2+) wave that propagated outward from the synapse within milliseconds and triggered lysosomal mobilization to the synapse, facilitating membrane repair and conferring resistance to CTL induced cytotoxicity. Inhibition of Ca(2+) flux and silencing of synaptotagmin VII limited synaptic lysosomal exposure and enhanced cytotoxicity. Multiplexed immunohistochemistry of patient melanoma nodules combined with automated image analysis showed that melanoma cells facing CD8(+) CTLs in the tumor periphery or peritumoral area exhibited significant lysosomal enrichment. Our results identified synaptic Ca(2+) entry as the definitive trigger for lysosomal deployment to the synapse upon CTL attack and highlighted an unpredicted defensive topology of lysosome distribution in melanoma nodules.