Jurkat T-Cell Antigen-Independent Elimination of PMA-Activated Neuroblastoma Cells Is Triggered by CCL2/CCR2, Depends Upon Lipid Raft LFA1/ICAM1 Immune Synapses, Is Mediated by m-TRAIL and Is Augmented by the TrkAIII Oncoprotein.

Maddalena Sbaffone, Ilaria Martelli, Paola Cipriani, Antonietta Rosella Farina, Lucia Annamaria Cappabianca, Andrew Reay Mackay

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Article in International journal of molecular sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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6 authors.

Maddalena SbaffoneDepartment of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67100 L'Aquila, Italy.ORCID 0000-0001-5770-084X

Ilaria MartelliDepartment of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67100 L'Aquila, Italy.ORCID 0009-0008-6884-4062

Paola CiprianiDepartment of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67100 L'Aquila, Italy.ORCID 0000-0002-2000-4661

Antonietta Rosella FarinaDepartment of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67100 L'Aquila, Italy.ORCID 0000-0003-0962-6088

Lucia Annamaria CappabiancaDepartment of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67100 L'Aquila, Italy.ORCID 0000-0002-9112-1750

Andrew Reay MackayDepartment of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67100 L'Aquila, Italy.ORCID 0000-0001-7096-3759

Funding

Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila 67100, Italy 07_DG_2025_02 and 07_DG_2025_11.

6 · The paper itself

Abstract

Advances in multimodal therapy for high-risk neuroblastomas (NBs) have plateaued, prompting therapeutic initiatives to harness the immune system. NBs, however, are immunologically "cold" and a significant challenge to immunotherapy. Here, in a Jurkat lymphocyte cytotoxicity model, we describe an antigen-independent, cell-mediated mechanism for eliminating NB cells, first detected in PMA-activated low pcDNA-SH-SY5Y and high TrkAIII-SH-SY5Y TrkAIII-expressing cells, which are resistant to Jurkat elimination under normal conditions. Characterization of this mechanism through live cell imaging, adhesion assays, RT-PCR, Western blotting and indirect IF, employing a variety of inhibitors, indicates that it initiates with PMA-induced NB cell CCL2 expression. This results in CCL2 promotion of Jurkat CCR2b expression, CCL2/CCR2b-mediated Jurkat LFA-1 activation and the formation of cytotoxic lipid-raft LFA1/ICAM-1 immune synapses, through which Jurkat m-TRAIL combines with PMA-enhanced NB cell DR5/TRAIL-R2 expression to induce NB cell apoptosis. This mechanism is enhanced by the NB-associated oncoprotein TrkAIII through Shp/Src-regulated c-FLIP sequester and is PD-L1/PD-1-independent and resistant to osteoprotegerin. It eliminates both non-

Indexed as

Immunological SynapsesNeuroblastomaT-Lymphocytes, CytotoxicApoptosisChemokine CCL2Coculture TechniquesHumansIntegrin beta ChainsIntercellular Adhesion Molecule-1Jurkat CellsMembrane MicrodomainsOsteoprotegerinReceptors, CCR2Receptors, TNF-Related Apoptosis-Inducing LigandReceptor, trkATetradecanoylphorbol AcetateCCL2 protein, humanCCR2 protein, humanChemokine CCL2ICAM1 protein, humanIntegrin beta ChainsIntercellular Adhesion Molecule-1ITGB2 protein, humanNTRK1 protein, humanOsteoprotegerinReceptors, CCR2Receptors, TNF-Related Apoptosis-Inducing LigandReceptor, trkATetradecanoylphorbol AcetateTNF-Related Apoptosis-Inducing LigandTNFRSF10B protein, humanTNFRSF11B protein, humanTNFSF10 protein, humanCCL2/CCR2-axiscFLIPJurkat T-cellsLFA-1/ICAM-1 immune synapsesneuroblastomaosteoprotegerinPD-1/PD-L1TRAILTRAIL receptorsTrkAIII

Identifiers

PMID41752106

DOI10.3390/ijms27041970

PMCPMC12940949

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