Data from: Chimeric antigen receptors that trigger phagocytosis

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（Chimeric Antigen Receptors，CARs）是一类可重编程T细胞以杀伤肿瘤细胞的合成受体。CAR-T细胞疗法的成功彰显了程序化免疫的应用前景，同时也提示将CAR策略拓展至其他免疫细胞谱系或具备临床价值。本研究构建了一类用于吞噬作用的嵌合抗原受体（Chimeric Antigen Receptors for Phagocytosis，CAR-Ps），可引导巨噬细胞吞噬包括肿瘤细胞在内的特定靶标。CAR-Ps由胞外抗体片段构成，可通过修饰实现对特定抗原的靶向调控。通过筛选一组吞噬受体胞内结构域，本研究发现Megf10与FcRɣ的胞质结构域可独立于其天然胞外结构域，强效诱导吞噬作用。实验结果表明，CAR-Ps可特异性吞噬抗原包被的合成颗粒以及完整的人类肿瘤细胞。添加串联式磷脂酰肌醇3-激酶（PI3K）招募结构域可提升肿瘤细胞的吞噬效率。最终实验证实，表达CAR-Ps的小鼠巨噬细胞可在共培养体系中将肿瘤细胞数量减少40%以上。