Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.
Department of Biomedical Engineering, Mork Family Department of Chemical Engineering and Materials Science, and Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
Integr Biol (Camb). 2020 May 21;12(5):109-121. doi: 10.1093/intbio/zyaa008.
Natural killer (NK) cells are part of the innate immune system and are capable of killing diseased cells. As a result, NK cells are being used for adoptive cell therapies for cancer patients. The activation of NK cell stimulatory receptors leads to a cascade of intracellular phosphorylation reactions, which activates key signaling species that facilitate the secretion of cytolytic molecules required for cell killing. Strategies that maximize the activation of such intracellular species can increase the likelihood of NK cell killing upon contact with a cancer cell and thereby improve efficacy of NK cell-based therapies. However, due to the complexity of intracellular signaling, it is difficult to deduce a priori which strategies can enhance species activation. Therefore, we constructed a mechanistic model of the CD16, 2B4 and NKG2D signaling pathways in NK cells to simulate strategies that enhance signaling. The model predictions were fit to published data and validated with a separate dataset. Model simulations demonstrate strong network activation when the CD16 pathway is stimulated. The magnitude of species activation is most sensitive to the receptor's initial concentration and the rate at which the receptor is activated. Co-stimulation of CD16 and NKG2D in silico required fewer ligands to achieve half-maximal activation than other combinations, suggesting co-stimulating these pathways is most effective in activating the species. We applied the model to predict the effects of perturbing the signaling network and found two strategies that can potently enhance network activation. When the availability of ligands is low, it is more influential to engineer NK cell receptors that are resistant to proteolytic cleavage. In contrast, for high ligand concentrations, inhibiting phosphatase activity leads to sustained species activation. The work presented here establishes a framework for understanding the complex, nonlinear aspects of NK cell signaling and provides detailed strategies for enhancing NK cell activation.
自然杀伤 (NK) 细胞是先天免疫系统的一部分，能够杀死患病细胞。因此，NK 细胞被用于癌症患者的过继细胞疗法。NK 细胞刺激受体的激活导致细胞内磷酸化反应级联，从而激活促进细胞杀伤所需细胞溶解分子分泌的关键信号物质。最大限度地激活这些细胞内物质的策略可以增加 NK 细胞与癌细胞接触时杀伤的可能性，从而提高 NK 细胞为基础的治疗的疗效。然而，由于细胞内信号的复杂性，很难事先推断出哪些策略可以增强物质的激活。因此，我们构建了一个 NK 细胞中 CD16、2B4 和 NKG2D 信号通路的机制模型，以模拟增强信号的策略。模型预测与已发表的数据进行拟合，并使用单独的数据集进行验证。模型模拟表明，当 CD16 途径受到刺激时，网络会强烈激活。物质激活的幅度对受体的初始浓度和受体被激活的速度最敏感。在计算机中，CD16 和 NKG2D 的共刺激需要更少的配体来实现一半的最大激活，这表明共刺激这些途径是最有效地激活物质的途径。我们将该模型应用于预测扰动信号网络的影响，发现了两种可以有效增强网络激活的策略。当配体的可用性较低时，设计对蛋白水解切割具有抗性的 NK 细胞受体更具影响力。相比之下，对于高浓度的配体，抑制磷酸酶活性会导致持续的物质激活。本文建立了一个理解 NK 细胞信号复杂、非线性方面的框架，并提供了增强 NK 细胞激活的详细策略。
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