Malignant features of head and neck squamous cell carcinoma (HNSCC) may be derived from the presence of stem-like cells that are characterized by uniquely high tumorigenic potential. These cancer stem cells (CSC) function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Although they are an appealing conceptual target, CSC-directed cancer therapies remain scarce. One promising CSC target is the IL6 pathway, which is strongly correlated with poor patient survival. In this study we created and validated a multiscale mathematical model to investigate the impact of cross-talk between tumor cell- and endothelial cell (EC)-secreted IL6 on HNSCC growth and the CSC fraction. We then predicted and analyzed the responses of HNSCC to tocilizumab (TCZ) and cisplatin combination therapy. The model was validated with in vivo experiments involving human ECs coimplanted with HNSCC cell line xenografts. Without artificial tuning to the laboratory data, the model showed excellent predictive agreement with the decrease in tumor volumes observed in TCZ-treated mice, as well as a decrease in the CSC fraction. This computational platform provides a framework for preclinical cisplatin and TCZ dose and frequency evaluation to be tested in future clinical studies. SIGNIFICANCE: A mathematical model is used to rapidly evaluate dosing strategies for IL6 pathway modulation. These results may lead to nonintuitive dosing or timing treatment schedules to optimize synergism between drugs.

中文翻译：

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In Silico模型可准确预测头颈癌对IL6的体内反应。

头颈部鳞状细胞癌（HNSCC）的恶性特征可能源于干细胞样细胞的存在，其特征是具有独特的高致瘤性。这些癌症干细胞（CSC）充当了肿瘤起始，治疗逃避，转移和复发的推定驱动器。尽管它们是吸引人的概念目标，但CSC指导的癌症治疗仍然很少。IL6途径是一种有前途的CSC靶标，该途径与患者的不良生存密切相关。在这项研究中，我们创建并验证了一个多尺度数学模型，以研究肿瘤细胞和内皮细胞（EC）分泌的IL6之间的串扰对HNSCC生长和CSC分数的影响。然后，我们预测并分析了HNSCC对tocilizumab（TCZ）和顺铂联合治疗的反应。该模型已通过体内实验验证，该实验涉及将人类EC与HNSCC细胞系异种移植物共植入。如果没有人为调整实验室数据，该模型显示出优异的预测一致性，与在TCZ处理的小鼠中观察到的肿瘤体积减少以及CSC分数减少有关。该计算平台为临床前顺铂和TCZ剂量和频率评估提供了框架，可在未来的临床研究中进行测试。重要性：一个数学模型可用于快速评估IL6途径调节的给药策略。这些结果可能导致不直观的给药或安排治疗计划以优化药物之间的协同作用。该模型显示出极好的预测一致性，与在TCZ处理的小鼠中观察到的肿瘤体积减少以及CSC分数减少有关。该计算平台为临床前顺铂和TCZ剂量和频率评估提供了框架，可在未来的临床研究中进行测试。重要性：数学模型可用于快速评估IL6途径调节的给药策略。这些结果可能导致不直观的给药或安排治疗计划以优化药物之间的协同作用。该模型显示出极好的预测一致性，与在TCZ处理的小鼠中观察到的肿瘤体积减少以及CSC分数减少有关。该计算平台为临床前顺铂和TCZ剂量和频率评估提供了框架，可在未来的临床研究中进行测试。重要性：数学模型可用于快速评估IL6途径调节的给药策略。这些结果可能导致不直观的给药或安排治疗计划以优化药物之间的协同作用。数学模型用于快速评估IL6途径调节的给药策略。这些结果可能导致不直观的给药或安排治疗计划以优化药物之间的协同作用。数学模型用于快速评估IL6途径调节的给药策略。这些结果可能导致不直观的给药或安排治疗计划以优化药物之间的协同作用。