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
Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
Sci Adv. 2025 May 23;11(21):eadr9331. doi: 10.1126/sciadv.adr9331. Epub 2025 May 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, CD40LCD8 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.
T细胞及其效应功能，特别是CD8 T细胞涉及穿孔素、颗粒酶、Fas配体（FasL）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）的典型细胞毒性，对肿瘤免疫至关重要。在此，我们揭示了一种以前未被识别的机制，即表达CD40L的CD8 T细胞在癌细胞中诱导细胞毒性的机制。在小鼠模型中，高达50%的肿瘤特异性CD8 T细胞表达CD40L，仅在CD8 T细胞中进行条件性CD40L缺失会导致肿瘤形成。从机制上讲，CD40L+ CD8 T细胞可通过触发半胱天冬酶-8激活在表达CD40的癌细胞中诱导细胞死亡。我们证明，对CD40信号诱导的细胞死亡具有抗性的基因特征与不同人类癌症队列中较差的生存率密切相关。我们的结果表明，CD40L是一种相当违反直觉的非典型细胞毒性因子，它补充了CD8 T细胞对抗癌症的能力，并有可能提高免疫疗法的疗效。
