School of Biomedical Informatics, The University of Texas Health science center at Houston, Houston, Texas, United States of America.
Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, North Carolina, United States of America.
PLoS Comput Biol. 2019 Sep 10;15(9):e1007344. doi: 10.1371/journal.pcbi.1007344. eCollection 2019 Sep.
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in American men. Androgen deprivation therapy (ADT) has become a standard treatment strategy for advanced PCa. Although a majority of patients initially respond to ADT well, most of them will eventually develop castration-resistant PCa (CRPC). Previous studies suggest that ADT-induced changes in the immune microenvironment (mE) in PCa might be responsible for the failures of various therapies. However, the role of the immune system in CRPC development remains unclear. To systematically understand the immunity leading to CRPC progression and predict the optimal treatment strategy in silico, we developed a 3D Hybrid Multi-scale Model (HMSM), consisting of an ODE system and an agent-based model (ABM), to manipulate the tumor growth in a defined immune system. Based on our analysis, we revealed that the key factors (e.g. WNT5A, TRAIL, CSF1, etc.) mediated the activation of PC-Treg and PC-TAM interaction pathways, which induced the immunosuppression during CRPC progression. Our HMSM model also provided an optimal therapeutic strategy for improving the outcomes of PCa treatment.
前列腺癌（PCa）是美国男性最常见的恶性肿瘤，也是癌症相关死亡的第二大主要原因。去势治疗（ADT）已成为晚期 PCa 的标准治疗策略。尽管大多数患者最初对 ADT 反应良好，但大多数患者最终将发展为去势抵抗性 PCa（CRPC）。先前的研究表明，ADT 诱导的 PCa 免疫微环境（mE）变化可能是导致各种治疗失败的原因。然而，免疫系统在 CRPC 发展中的作用仍不清楚。为了系统地了解导致 CRPC 进展的免疫反应，并通过计算预测最佳的治疗策略，我们开发了一个由 ODE 系统和基于主体的模型（ABM）组成的 3D 混合多尺度模型（HMSM），以在定义的免疫系统中操纵肿瘤生长。通过我们的分析，我们揭示了关键因素（例如 WNT5A、TRAIL、CSF1 等）介导了 PC-Treg 和 PC-TAM 相互作用途径的激活，从而在 CRPC 进展过程中诱导了免疫抑制。我们的 HMSM 模型还为改善 PCa 治疗效果提供了最佳治疗策略。
