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合成双重共刺激增加了HIT和tcr靶向细胞治疗的效力

原文发布日期：2024-03-19

英文摘要：

摘要翻译：

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合成双重共刺激增加了HIT和tcr靶向细胞治疗的效力

Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies

原文发布日期：2024-03-19

英文摘要：

Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies.

摘要翻译：

融合抗原受体T细胞在血液恶性肿瘤治疗中取得了显著进展。基于T细胞抗原受体的细胞疗法尚未取得同样效果。值得注意的是，融合抗原受体不仅靶向特定抗原，还通过与抗原识别过程中激活的辅助信号通路重新编程了T细胞功能。我们在这里展示，由CD80外域和4-1BB胞内域组成的融合受体称为80BB，既作为配体又作为受体，通过与抗原识别联合作用，激活了CD28和4-1BB信号通路，从而提高了人类表皮白细胞抗原独立的T细胞或T细胞融合蛋白(TCR)-工程化T细胞及肿瘤浸润淋巴细胞的抗肿瘤活性。此外，80BB还作为转换受体，在CTLA4抑制剂与其结合时提供促agonsic 4-1BB共刺激作用。通过在一个抗原agnostic合成受体中集成多种辅助信号通路特征，80BB是一个有潜力的工具，能够在针对免疫治疗的各种靶向疗法中持续维持CD3依赖性T细胞应答。