Article Dans Une Revue Science Advances Année : 2022

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

Sabina Müller

Résumé

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.

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hal-04990946 , version 1 (22-05-2025)

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Liza Filali, Marie-Pierre Puissegur, Kevin Cortacero, Sylvain Cussat-Blanc, Roxana Khazen, et al.. Ultrarapid lytic granule release from CTLs activates Ca 2+ -dependent synaptic resistance pathways in melanoma cells. Science Advances , 2022, 8 (7), 19 p. ⟨10.1126/sciadv.abk3234⟩. ⟨hal-04990946⟩
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