Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
Elife. 2018 Jun 4;7:e36688. doi: 10.7554/eLife.36688.
Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%.
嵌合抗原受体 (CAR) 是一种能够重新编程 T 细胞以杀伤癌症的人工受体。CAR-T 细胞疗法的成功突出了程序性免疫的潜力，并表明将 CAR 策略应用于其他免疫细胞谱系可能是有益的。在这里，我们设计了一系列能够引导巨噬细胞吞噬特定靶标（包括癌细胞）的嵌合抗原受体用于吞噬 (CAR-P)。CAR-P 由一个能够被修饰以将 CAR-P 活性导向特定抗原的细胞外抗体片段组成。通过筛选一组吞噬受体细胞内结构域，我们发现 Megf10 和 FcRγ 的胞质结构域能够独立于其天然的细胞外结构域，强有力地触发吞噬作用。我们证明，CAR-P 能够驱动对包被抗原的合成颗粒和整个人类癌细胞的特异性吞噬。添加串联 PI3K 募集结构域可增加癌细胞的吞噬作用。最后，我们证明表达 CAR-P 的小鼠巨噬细胞通过共培养减少了超过 40%的癌细胞数量。
