Mathematical modelling of trastuzumab-induced immune response in an in vivo murine model of HER2+breast cancer
Mathematical modelling of trastuzumab-induced immune response in an in vivo murine model of HER2+breast cancer
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DOI：
10.1093/imammb/dqy014
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发表时间：
2019-09-01
影响因子：
1.1
通讯作者：
Sorace, Anna G.
中科院分区：
文献类型：
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作者：
Jarrett, Angela M.;Bloom, Meghan J.;Sorace, Anna G.
本研究的目的是开发一种综合的数学实验方法，以了解免疫系统与曲妥珠单抗对过度表达人表皮生长因子受体2 （HER2+）的乳腺癌的影响之间的相互作用。建立了一个耦合的常微分方程系统来描述肿瘤生长的时间变化，以及肿瘤内免疫反应、血管、坏死和缺氧的变化。该数学模型是根据从HER2+乳腺癌小鼠模型的影像学或组织学中获得的肿瘤体积、血管、坏死和缺氧的一系列实验数据进行校准的。灵敏度分析表明，模型分量对13个参数中的12个参数敏感，但考虑到参数值的不确定性，模型模拟结果与实验数据仍然吻合。给定初始条件，数学模型预测随着时间的推移，治疗动物的免疫浸润增加。免疫荧光染色结果显示，与对照组相比，治疗肿瘤的总组织中cd11c和F4/80（树突状细胞和/或巨噬细胞表达的蛋白质）的共染色增加，从而验证了这一预测（p < 0.03）。我们假设所提出的数学-实验方法可用于阐明曲妥珠单抗诱导的肿瘤反应和免疫系统之间的驱动相互作用，这些相互作用驱动血管系统的稳定，同时减少肿瘤生长-数学模型揭示的结论不能单独从实验数据中推导出来。
The goal of this study is to develop an integrated, mathematical-experimental approach for understanding the interactions between the immune system and the effects of trastuzumab on breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2+). A system of coupled, ordinary differential equations was constructed to describe the temporal changes in tumour growth, along with intratumoural changes in the immune response, vascularity, necrosis and hypoxia. The mathematical model is calibrated with serially acquired experimental data of tumour volume, vascularity, necrosis and hypoxia obtained from either imaging or histology from a murine model of HER2+ breast cancer. Sensitivity analysis shows that model components are sensitive for 12 of 13 parameters, but accounting for uncertainty in the parameter values, model simulations still agree with the experimental data. Given theinitial conditions, the mathematical model predicts an increase in the immune infiltrates over time in the treated animals Immunofluorescent staining results are presented that validate this prediction by showing an increased co-staining of CD11 c and F4/80 (proteins expressed by dendritic cells and/or macrophages) in the total tissue for the treated tumours compared to the controls (p < 0.03). We posit that the proposed mathematical-experimental approach can be used to elucidate driving interactions between the trastuzumab-induced responses in the tumour and the immune system that drive the stabilization of vasculature while simultaneously decreasing tumour growth-conclusions revealed by the mathematical model that were not deducible from the experimental data alone.