Systematically understanding the immunity leading to CRPC progression

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 t...

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Bibliographic Details
Published in:	PLoS computational biology 2019-09, Vol.15 (9), p.e1007344-e1007344
Main Authors:	Ji, Zhiwei, Zhao, Weiling, Lin, Hui-Kuan, Zhou, Xiaobo
Format:	Article
Language:	eng
Subjects:	Androgen Antagonists - therapeutic use Androgens Angiogenesis Antigens Bioinformatics Biology and life sciences Cancer Cancer therapies Care and treatment Castration Cell division Computational Biology Computer Simulation Cytokines Cytokines - immunology Death Deprivation Development and progression Enzalutamide Gene amplification Health aspects Humans Immune system Immunity Immunosuppression Immunotherapy Informatics Lymph Nodes - immunology Lymphatic system Lymphocytes T Male Malignancy Mathematical models Medicine and Health Sciences Models, Immunological Ordinary differential equations Prostate cancer Prostatic Neoplasms, Castration-Resistant - drug therapy Prostatic Neoplasms, Castration-Resistant - immunology Scale models Signal transduction Stem cells Strategy T-Lymphocytes, Regulatory - immunology Three dimensional models Tumors Wnt protein
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Summary:	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.
ISSN:	1553-7358 1553-734X 1553-7358