基于异质性的肿瘤免疫系统动力学研究

Cancer is one of the world's most serious diseases causing the major public health problems, and tumor heterogeneity is its major feature. The current immunotherapy that activates the host's immune system against cancer provides new hope for patients, but tumor heterogeneity is the main obstacle to effective cancer treatment. The composition of immune cells in the tumor microenvironment is highly diverse, and the mutual interactions between tumor cells and immune cells are very complex and constantly changing. As the rapid development of immunology and molecular biology, we aim to develop several new mathematical models to capture and investigate the interactions among tumor cell and immune cell based on the heterogeneity in the tumor microenvironment. The dual roles (suppression and promotion) of immune cells in tumor development and progression will be considered in the modeling process. First, we will develop a tumor immune system interaction model to consider the heterogeneity of immune cells, such as, helper T cells (Th1 and Th2), macrophages (M1 and M2), cytotoxic T lymphocytes (CTLs) and so on. Secondly, we will construct the reaction diffusion equations to model the spatial spread and dispersion of immune cells and tumor cells. Finally, we will study the influence of immune activation delays and immunotherapy on the dynamics of system. And we will estimate the parameters by fitting to the experimental data and correct the corresponding models. This project can provide scientific evidence to help understand the mechanism and pathogenesis of cancer, prevent and treat cancer.

癌症是全球范围内严重危害人类生命健康的重大疾病，其重要特征是肿瘤异质性。当前免疫疗法给癌症患者带来了新的曙光，但肿瘤异质性一直是攻克癌症的一大障碍。本项目拟针对肿瘤免疫微环境中细胞组成高度异质性和细胞扩散空间异质性，通过构建数学模型来研究肿瘤细胞和免疫细胞之间的相互作用关系，揭示异质性对肿瘤生长与转移的影响。主要研究内容包括：1）构建具有细胞组成高度异质性的肿瘤免疫系统动力学模型，来模拟各种免疫细胞如辅助性T细胞Th1和Th2，巨噬细胞M1和M2，细胞毒性T淋巴细胞等与肿瘤细胞之间的相互作用关系。2）在已有的肿瘤免疫系统模型基础上，引入细胞扩散空间异质性，构建肿瘤免疫系统相互作用的时空模型。3）研究免疫时滞和免疫治疗等因素对模型动力学的影响，以及利用相关实验数据估计模型参数，修正所建模型。研究结果将为人们更好地理解癌症发病机理以及预防和治疗癌症提供科学依据。

癌症（恶性肿瘤）是威胁人类生命健康的重大公共卫生问题，而肿瘤的异质性与癌症能否攻克具有很大的关系。研究表明肿瘤的异质性越高，免疫系统抗癌的能力就越弱，癌症发展的就越快。基于肿瘤微环境中细胞组成高度异质性和细胞扩散空间异质性，构建了若干数学模型来研究了肿瘤与免疫系统的相互作用关系，揭示了异质性对肿瘤免疫系统的影响，取得了一系列有意义的理论和应用研究结果。主要研究进展和阶段性成果：1）构建了具有肿瘤细胞、M1和M2巨噬细胞的数学模型，研究了巨噬细胞M2/M1比率、M1和M2巨噬细胞间的转化率等重要参数对模型的影响。2）构建了高维肿瘤免疫动力学模型，研究了调节性T细胞和转化生长因子的作用，评估了免疫治疗的疗效。3）研究了分布时滞对肿瘤免疫系统动力学的影响，发现了时滞的双重作用使平衡点失去稳定和促进稳定。4）研究了具有细胞异质性的高度非线性动力学模型，发现了系统有双稳现象，以及稳定的周期环。5）构建了具有细胞扩散空间异质性的肿瘤免疫系统动力学模型，研究了行波解的存在性与稳定性，探讨了免疫细胞空间扩散对肿瘤生长和转移的影响。利用极大似然估计法拟合数据，估计了肿瘤的生长率，阐述了模型研究结果的生物意义和实际应用。

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