Ultrarapid lytic granule release from CTLs activates Ca2+-dependent synaptic resistance pathways in melanoma cells

Liza Filali, Marie Pierre Puissegur, Kevin Cortacero, Sylvain Cussat-Blanc, Roxana Khazen, Nathalie Van Acker, François Xavier Frenois, Arnaud Abreu, Laurence Lamant, Nicolas Meyer, Béatrice Vergier, Sabina Müller, Brienne McKenzie, Salvatore Valitutti

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

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 Ca2+ 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 Ca2+ 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 Ca2+ 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.

Original languageEnglish
Pages (from-to)eabk3234
JournalScience advances
Volume8
Issue number7
DOIs
Publication statusPublished - 18 Feb 2022

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