A1 Refereed original research article in a scientific journal
CD8+T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells
Authors: Schiele, Phillip; Japp, Alberto Sada; Stark, Regina; Sattelberg, Joanna J.; Nikolaou, Christos; Kornhuber, Gereon; Abbasi, Parya; Ding, Nina; Rosnev, Stanislav; Meinke, Stefan; Mühle, Kerstin; Loyal, Lucie; Braun, Julian; Dingeldey, Manuela; Durlanik, Sibel; Matzmohr, Nadine; Ponikwicka-Tyszko, Donata; Wolczynski, Slawomir; Rahman, Nafis A.; Taniuchi, Ichiro; Schlickeiser, Stephan; Giesecke-Thiel, Claudia; Blankenstein, Thomas; Na, Il-Kang; Thiel, Andreas; Frentsch, Marco
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Publishing place: WASHINGTON
Publication year: 2025
Journal: Science Advances
Journal name in source: SCIENCE ADVANCES
Journal acronym: SCI ADV
Article number: eadr9331
Volume: 11
Issue: 21
Number of pages: 14
ISSN: 2375-2548
eISSN: 2375-2548
DOI: https://doi.org/10.1126/sciadv.adr9331
Web address : https://doi.org/10.1126/sciadv.adr9331
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/498669067
T cells and their effector functions, in particular the canonical cytotoxicity of CD8+T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8+T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8+T cells expressed CD40L, and conditional CD40L ablation in CD8+T cells alone led to tumor formation. Mechanistically, CD40L+CD8+ T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8+T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.
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Funding information in the publication:
This work was supported by Wilhelm-Sander-Stiftung (2019.047.1 to M.F. and I.-K. N.) and the Deutsche Forschungsgemeinschaft [collaborative research centre SFB TR36 (to T.B., A.T., and I.-K. N.), DFG Th 806/5-1 (to A.T.), DFG 546141032 (to M.F. and I.-K. N.), and the European Union through ERC Advanced Grant 882963 (to T.B.) supported this work.
