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
Main Authors: Ji, Zhiwei, Zhao, Weiling, Lin, Hui-Kuan, Zhou, Xiaobo
Format: Article
Language:English
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
DOI:10.1371/journal.pcbi.1007344