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@ARTICLE{Schiele:301513,
author = {P. Schiele and A. S. Japp and R. Stark and J. J. Sattelberg
and C. Nikolaou and G. Kornhuber and P. Abbasi and N. Ding
and S. Rosnev and S. Meinke and K. Mühle and L. Loyal and
J. Braun and M. Dingeldey and S. Durlanik and N. Matzmohr
and D. Ponikwicka-Tyszko and S. Wolczynski and N. A. Rahman
and I. Taniuchi and S. Schlickeiser and C. Giesecke-Thiel
and T. Blankenstein and I.-K. Na$^*$ and A. Thiel and M.
Frentsch},
title = {{CD}8+ {T} cell-derived {CD}40{L} mediates noncanonical
cytotoxicity in {CD}40-expressing cancer cells.},
journal = {Science advances},
volume = {11},
number = {21},
issn = {2375-2548},
address = {Washington, DC [u.a.]},
publisher = {Assoc.},
reportid = {DKFZ-2025-01050},
pages = {eadr9331},
year = {2025},
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 = {CD8-Positive T-Lymphocytes: immunology / CD8-Positive
T-Lymphocytes: metabolism / CD40 Ligand: metabolism / CD40
Ligand: genetics / CD40 Ligand: immunology / Animals /
Humans / CD40 Antigens: metabolism / CD40 Antigens: genetics
/ Mice / Cell Line, Tumor / Neoplasms: immunology /
Neoplasms: metabolism / Neoplasms: pathology / Neoplasms:
genetics / Cytotoxicity, Immunologic / Signal Transduction /
Caspase 8: metabolism / CD40 Ligand (NLM Chemicals) / CD40
Antigens (NLM Chemicals) / Caspase 8 (NLM Chemicals)},
cin = {BE01},
ddc = {500},
cid = {I:(DE-He78)BE01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40397730},
doi = {10.1126/sciadv.adr9331},
url = {https://inrepo02.dkfz.de/record/301513},
}