Natural killer (NK) cells play an important role in cancer immunosurveillance and therapy. However, the target selectivity of NK cell activity is still poorly understood. Here, we used live-cell reporters to unravel differential epithelial cancer target killing by primary human NK cells. We found highly variable fractions of killing by distinct NK cell cytotoxic modes that were not determined by NK ligand expression. Rather, epithelial plasma membrane dynamics driven by ROCK-mediated blebs and/or Rac1-mediated lamellipodia promoted necrotic mode in preference to the apoptotic mode of killing. Inhibition of granzyme B and key necroptosis regulators RIP1, RIP3, and MLKL significantly attenuated the necrotic killing, revealing a novel NK cell cytotoxic pathway by granzyme-induced necroptosis that conferred target selectivity. Our results not only elucidate a new NK cell effector mechanism but also suggest that tissue microenvironment and oncogenic signaling pathways that promote membrane dynamics, e.g., Rac1 and Rho/ROCK, could be exploited to enhance proinflammatory NK cell killing.

中文翻译：

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Rac1/ROCK驱动的膜动力学通过颗粒酶诱导的坏死性凋亡促进自然杀伤细胞的细胞毒性


自然杀伤（NK）细胞在癌症免疫监视和治疗中发挥着重要作用。然而，NK细胞活性的靶点选择性仍然知之甚少。在这里，我们使用活细胞报告基因来揭示原代人类 NK 细胞对上皮癌靶标的不同杀伤作用。我们发现不同 NK 细胞细胞毒性模式的杀伤分数存在很大差异，这些模式并非由 NK 配体表达决定。相反，由 ROCK 介导的泡和/或 Rac1 介导的片状伪足驱动的上皮质膜动力学促进了坏死模式，而不是凋亡模式的杀伤。颗粒酶 B 和关键坏死性凋亡调节因子 RIP1、RIP3 和 MLKL 的抑制显着减弱了坏死性杀伤，揭示了颗粒酶诱导的坏死性凋亡产生的新的 NK 细胞细胞毒性途径，从而赋予了靶点选择性。我们的结果不仅阐明了新的 NK 细胞效应机制，还表明促进膜动力学的组织微环境和致癌信号通路（例如 Rac1 和 Rho/ROCK）可用于增强促炎 NK 细胞杀伤。