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| Item Type: | Article |
|---|---|
| Title: | CD8(+) T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells |
| Creators Name: | Schiele, P., Sada Japp, A., Stark, R., Sattelberg, J.J., Nikolaou, C., Kornhuber, G., Abbasi, P., Ding, N., Rosnev, S., Meinke, S., Mühle, K., Loyal, L., Braun, J., Dingeldey, M., Durlanik, S., Matzmohr, N., Ponikwicka-Tyszko, D., Wolczynski, S., Rahman, N.A., Taniuchi, I., Schlickeiser, S., Giesecke-Thiel, C., Blankenstein, T., Na, I.K., Thiel, A. and Frentsch, M. |
| Abstract: | 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. |
| Keywords: | CD40 Antigens, CD40 Ligand, CD8-Positive T-Lymphocytes, Caspase 8, Immunologic Cytotoxicity, Neoplasms, Signal Transduction, Tumor Cell Line, Animals, Mice |
| Source: | Science Advances |
| ISSN: | 2375-2548 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 11 |
| Number: | 21 |
| Page Range: | eadr9331 |
| Date: | 23 May 2025 |
| Official Publication: | https://doi.org/10.1126/sciadv.adr9331 |
| PubMed: | View item in PubMed |
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