肿瘤细胞治疗研究
英文原题：Engineering NK and T cells with metabolite-sensing receptors to target solid tumors.
这些数据表明，可以对代谢物感知进行重编程，以获得生化引导的空间靶向细胞，为治疗干预创造了新的可能性。
自然杀伤（NK）细胞和T细胞需要浸润实体瘤才能将其清除。在此，我们展示了可利用代谢物感应受体调动NK细胞和T细胞进入实体瘤的可编程机制。利用NK-92细胞进行的体内和体外CRISPR激活筛选鉴定出GPR183、GPR84、GPR34和GPR18为对乳腺癌和卵巢癌浸润及趋化作用最强的增强因子。这些受体虽然在有限的细胞环境中内源性表达，但在NK细胞和T细胞中表达这些受体可驱动细胞向癌细胞释放的因子迁移，并以配体依赖的方式改变NK细胞的转录组。在NK细胞、嵌合抗原受体（CAR）NK细胞和CAR T细胞中表达GPR183可增加肿瘤浸润和控制。同样，在小鼠T细胞中表达GPR183可增强免疫健全小鼠中的肿瘤清除。这些数据表明，代谢物感应可被重编程以获得生化引导的空间靶向细胞，为治疗干预创造了新的可能性。
Natural killer (NK) cells and T cells need to infiltrate solid tumors to eradicate them. Here we show programmable mechanisms that can mobilize NK and T cells to solid tumors using metabolite-sensing receptors. In vivo and in vitro CRISPR activation screens using NK-92 cells identified GPR183, GPR84, GPR34 and GPR18 as top enhancers of infiltration and chemotaxis to breast and ovarian cancers. While endogenously expressed in restricted cellular contexts, expressing these receptors in NK and T cells drives migration to factors released by cancer cells and alters the NK cell transcriptome in a ligand-dependent manner. Expressing GPR183 in NK, chimeric antigen receptor (CAR) NK and CAR T cells increased tumor infiltration and control. Likewise, expressing GPR183 in mouse T cells increased tumor eradication in immunocompetent mice. These data show that metabolite sensing can be rewired to obtain biochemically guided spatially targeted cells, creating new possibilities for therapeutic intervention.
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