Global stability and parameter analysis reinforce therapeutic targets of PD-L1-PD-1 and MDSCs for glioblastoma.
Global stability and parameter analysis reinforce therapeutic targets of PD-L1-PD-1 and MDSCs for glioblastoma.
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整体稳定性和参数分析加强了PD-L1-PD-1和MDSCs治疗胶质母细胞瘤的靶点。
DOI：
10.1007/s00285-023-02027-y
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发表时间：
2023-12-15
影响因子：
1.9
通讯作者：
中科院分区：
文献类型：
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作者：
胶质母细胞瘤（GBM）是一种侵袭性原发性脑癌，目前治疗效果最低。像其他癌症一样，PD-L1-PD-1免疫检查点复合物的免疫抑制是胶质瘤细胞逃避免疫系统的重要轴。骨髓源性抑制细胞（MDSCs）被募集到胶质瘤微环境中，也通过抑制T细胞功能促进免疫抑制的GBM微环境。在本文中，我们提出了胶质瘤细胞、T细胞和MDSCs的gbm特异性肿瘤免疫常微分方程模型，为这些细胞之间的相互作用提供理论见解。平衡和稳定性分析表明，在一定条件下存在唯一的局部稳定的有瘤平衡和无瘤平衡。此外，当T细胞激活和T细胞的肿瘤杀伤率克服肿瘤生长、PD-L1-PD-1和MDSCs对T细胞的抑制以及T细胞死亡率时，无瘤平衡是全局稳定的。分岔分析表明，包括手术切除和靶向PD-L1-PD1复合物和MDSCs引起的免疫抑制的治疗方案导致系统趋于无肿瘤平衡。利用一组临床前实验数据，我们实现了近似贝叶斯计算（ABC）拒绝方法来构建估计模型参数的概率密度分布。这些分布为使用扩展傅立叶振幅灵敏度测试进行全局灵敏度分析提供了适当的搜索曲线。结合ABC方法的敏感性结果表明，肿瘤负荷驱动因素（T细胞的肿瘤生长速度和承载能力以及肿瘤杀伤率）与PD-L1-PD-1免疫检查点和MDSC对T细胞的抑制这两种模型免疫抑制形式之间存在参数交互作用。因此，应该探索免疫检查点抑制剂联合靶向MDSCs抑制机制的治疗方法。在线版本包含补充材料，可在10.1007/s00285-023-02027-y获得。
Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the approximate Bayesian computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended fourier amplitude sensitivity test. Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored. The online version contains supplementary material available at 10.1007/s00285-023-02027-y.
影响因子：
2.9
作者：
Bryukhovetskiy I
通讯作者：
Bryukhovetskiy I