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.

嵌合抗原受体 T 细胞极大地改善了血液恶性肿瘤的治疗。基于 T 细胞抗原受体 (TCR) 的细胞疗法尚未取得可比的结果。重要的是，嵌合抗原受体不仅靶向选定的抗原，而且还通过它们在抗原识别时参与的共刺激途径重新编程 T 细胞功能。我们在此表明​​，包含 CD80 胞外域和 4-1BB 胞质结构域的融合受体（称为 80BB）既可作为配体又可作为受体参与 CD28 和 4-1BB 通路，从而增强人类白细胞抗原的抗肿瘤效力。独立 TCR (HIT) 受体或 TCR 工程 T 细胞和肿瘤浸润淋巴细胞。此外，80BB 充当开关受体，在与抑制性 CTLA4 分子连接后提供激动性 4-1BB 共刺激。通过将多种共刺激特征结合在一个与抗原无关的合成受体中，80BB 是一种很有前景的工具，可以在多种靶向免疫疗法中维持 CD3 依赖性 T 细胞反应。