Chimeric antigen receptors that trigger phagocytosis.
Chimeric antigen receptors that trigger phagocytosis.
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DOI：
10.7554/elife.36688
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发表时间：
2018-06-04
期刊：
影响因子：
7.7
通讯作者：
Vale RD
中科院分区：
文献类型：
--
作者：
Morrissey MA;Williamson AP;Steinbach AM;Roberts EW;Kern N;Headley MB;Vale RD
嵌合抗原受体(CARS)是一种合成的受体，可以重新编程T细胞来杀死癌症。CAR-T细胞疗法的成功突出了程序性免疫的前景，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，我们设计了一系列嵌合抗原吞噬受体(CAR-Ps)，引导巨噬细胞吞噬包括癌细胞在内的特定靶点。CAR-P由一段胞外抗体片段组成，可以对其进行修饰以将CAR-P活性导向特定的抗原。通过筛选一组吞噬受体胞内结构域，我们发现MEGF10和FcRɣ的胞内结构域不依赖于它们天然的胞外结构域而强烈地触发吞噬。我们发现，CAR-P能驱动包被抗原的合成颗粒和整个人类癌细胞的特异性吞噬。串联PI3K募集结构域的增加增加了癌细胞的吞噬。最后，我们发现，表达CAR-P的小鼠巨噬细胞在共培养中减少了40%以上的癌细胞数量。我们的免疫系统不断地巡视我们的身体，寻找清除癌细胞和有害微生物的方法。它可以发现这些威胁，因为它识别危险细胞表面的某些信号。然而，癌细胞通常会想办法“躲避”我们的免疫系统。嵌合抗原受体，或CARS，是在实验室设计的受体，用于附着在癌细胞上发现的特定蛋白质。这些受体告诉T细胞等免疫细胞攻击癌症。携带汽车的T细胞已经被用于治疗血癌患者。然而，这些免疫细胞不擅长穿透实体肿瘤杀死里面的细胞，这限制了它们的使用。巨噬细胞是一组免疫细胞，它们可以进入肿瘤内部，并向其他免疫系统无法到达的癌症转移。它们通过“吞噬”有害细胞来保护我们的身体。那么，是否有可能使用CARS对巨噬细胞进行编程，以‘吃掉’癌细胞呢？Morrissey，Williamson等人。创造了一种新型汽车，命名为CAR-P，并将其引入巨噬细胞。然后，这些细胞能够识别和攻击被癌细胞上发现的蛋白质覆盖的珠子。这种经过修饰的巨噬细胞还可以通过“咬”甚至“吃”来限制培养皿中活的癌细胞的生长。虽然这些结果在实验室是有希望的，但下一步是测试这些重新编程的巨噬细胞是否能够识别和抗击活动物的癌症。
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%. Our immune system constantly patrols our body, looking to eliminate cancerous cells and harmful microbes. It can spot these threats because it recognizes certain signals at the surface of dangerous cells. However, cancer cells often find ways to ‘hide’ from our immune system. Chimeric antigen receptors, or CARs, are receptors designed in a laboratory to attach to specific proteins that are found on a cancer cell. These receptors tell immune cells, such as T cells, to attack cancers. T cells that carry CARs are already used to treat people with blood cancers. Yet, these immune cells are not good at penetrating a solid tumor to kill the cells inside, which limits their use. Macrophages are a group of immune cells that can make their way inside tumors and travel to cancers that the rest of the immune system cannot reach. They defend our body by ‘swallowing’ harmful cells. Would it then be possible to use CARs to program macrophages to ‘eat’ cancer cells? Morrissey, Williamson et al. created a new type of CARs, named CAR-P, and introduced it in macrophages. These cells were then able to recognize and attack beads covered in proteins found on cancer cells. The modified macrophages could also limit the growth of live cancer cells in a dish by ‘biting’ and even ‘eating’ them. While these results are promising in the laboratory, the next step is to test whether these reprogrammed macrophages can recognize and fight cancers in living animals.