CD8 + T cell–derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells
- Phillip Schiele
- Alberto Sada Japp
- Regina Stark
- Joanna J. Sattelberg
- Christos Nikolaou
- Gereon Kornhuber
- Parya Abbasi
- Nina Ding
- Stanislav Rosnev
- Stefan Meinke
- Kerstin Mühle
- Lucie Loyal
- Julian Braun
- Manuela Dingeldey
- Sibel Durlanik
- Nadine Matzmohr
- Donata Ponikwicka-Tyszko
- Slawomir Wolczynski
- Nafis A. Rahman
- Ichiro Taniuchi
- Stephan Schlickeiser
- Claudia Giesecke-Thiel
- Thomas Blankenstein
- Il-Kang Na
- Andreas Thiel
- Marco Frentsch
2025-05-21
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.