Kwon Hyung-Joon, Kim Nayoung, Kim Hun Sik
Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Exp Mol Med. 2017 Mar 31;49(3):e311. doi: 10.1038/emm.2017.42.
Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor-ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer.
自然杀伤（NK）细胞因其对癌细胞相对于正常健康细胞具有天然选择性，作为癌症治疗中有前景的治疗工具而备受关注。凭借一系列进化而来以感知细胞变化的受体，NK细胞通过产生细胞因子和趋化因子并发挥直接细胞溶解活性，为抵御癌细胞提供早期保护。这些效应功能由通过多种受体 - 配体相互作用传递的信号控制，但静止NK细胞仅激活单一激活受体无法实现这些功能。相反，由于细胞内在抑制机制，它们需要共同激活使用不同信号模块的不同激活受体。协同受体的冗余性以及单一类别的抑制性受体对NK细胞功能的抑制表明，存在通过不同受体控制NK细胞激活的共同检查点。这些分子检查点将成为治疗靶点，以利用NK细胞对表达NK细胞受体异质配体的多种癌细胞的作用。最近在理解NK细胞激活方面的进展揭示了这一类中有前景的候选靶点。靶向此类分子检查点将通过降低激活阈值促进NK细胞激活，从而提供优化NK细胞对癌症反应性的治疗策略。
