CD8 +细胞毒性T淋巴细胞与肿瘤细胞协同进化动力学的离散和连续模型
Discrete and continuum models for the coevolutionary dynamics between CD8+ cytotoxic T lymphocytes and tumour cells
摘要：
我们提出了一个基于个体的模型CD 8+细胞毒性T淋巴细胞（CTL）和肿瘤细胞之间的协同进化动力学。在这个模型中，每个细胞被视为一个单独的代理，其表型状态是由一个离散变量建模。对于肿瘤细胞，该变量代表抗原表达谱的参数化，而对于CTL，其代表T细胞受体（TCR）的靶抗原的参数化。我们正式推导出这种基于个体的模型的确定性连续极限，该模型包括肿瘤细胞表型分布的非局部偏微分方程和CTL表型分布的积分微分方程。找到了与生物学相关的连续模型方程的齐次稳态解，并对这些稳态解进行了线性稳定性分析，以确定可能导致免疫竞争结果不同和肿瘤细胞与CTL表型协同进化模式出现的模型参数条件。我们报告的个人为基础的模型的计算结果，并表明，它们之间有一个很好的协议和连续体模型的分析和数值结果。这些结果揭示了不同参数影响肿瘤细胞和CTL之间的共同进化动力学的方式。此外，它们支持TCR-肿瘤抗原结合亲和力可能是免疫治疗的良好干预靶标的想法，并为旨在工程化TCR以塑造其对癌症靶标的亲和力的抗癌治疗的发展提供理论基础。
英文摘要：
We present an individual-based model for the coevolutionary dynamics between CD8+ cytotoxic T lymphocytes (CTLs) and tumour cells. In this model, every cell is viewed as an individual agent whose phenotypic state is modelled by a discrete variable. For tumour cells this variable represents a parameterisation of the antigen expression profiles, while for CTLs it represents a parameterisation of the target antigens of T-cell receptors (TCRs). We formally derive the deterministic continuum limit of this individual-based model, which comprises a non-local partial differential equation for the phenotype distribution of tumour cells coupled with an integro-differential equation for the phenotype distribution of CTLs. The biologically relevant homogeneous steady-state solutions of the continuum model equations are found. The linear-stability analysis of these steady-state solutions is then carried out in order to identify possible conditions on the model parameters that may lead to different outcomes of immune competition and to the emergence of patterns of phenotypic coevolution between tumour cells and CTLs. We report on computational results of the individual-based model, and show that there is a good agreement between them and analytical and numerical results of the continuum model. These results shed light on the way in which different parameters affect the coevolutionary dynamics between tumour cells and CTLs. Moreover, they support the idea that TCR-tumour antigen binding affinity may be a good intervention target for immunotherapy and offer a theoretical basis for the development of anti-cancer therapy aiming at engineering TCRs so as to shape their affinity for cancer targets.
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