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Rhodes2019 - Immune-Mediated theory of Metastasis

ABSTRACT: Abstract: Accumulating experimental and clinical evidence suggest that the immune response to cancer is not exclusively anti-tumor. Indeed, the pro-tumor roles of the immune system - as suppliers of growth and pro-angiogenic factors or defenses against cytotoxic immune attacks, for example - have been long appreciated, but relatively few theoretical works have considered their effects. Inspired by the recently proposed "immune-mediated" theory of metastasis, we develop a mathematical model for tumor-immune interactions at two anatomically distant sites, which includes both anti- and pro-tumor immune effects, and the experimentally observed tumor-induced phenotypic plasticity of immune cells (tumor "education" of the immune cells). Upon confrontation of our model to experimental data, we use it to evaluate the implications of the immune-mediated theory of metastasis. We find that tumor education of immune cells may explain the relatively poor performance of immunotherapies, and that many metastatic phenomena, including metastatic blow-up, dormancy, and metastasis to sites of injury, can be explained by the immune-mediated theory of metastasis. Our results suggest that further work is warranted to fully elucidate the pro-tumor effects of the immune system in metastatic cancer.

SUBMITTER: Szeyi Ng

PROVIDER: BIOMD0000000926 | BioModels | 2020-03-28

REPOSITORIES: BioModels

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Project description:The paper describes a model on the size of pancreatic tumour. Created by COPASI 4.25 (Build 207) This model is described in the article: Modeling Pancreatic Cancer Dynamics with Immunotherapy Xiaochuan Hu, Guoyi Ke and Sophia R.-J. Jang Bulletin of Mathematical Biology (2019) 81:1885–1915 Abstract: We develop a mathematical model of pancreatic cancer that includes pancreatic cancer cells, pancreatic stellate cells, effector cells and tumor-promoting and tumor- suppressing cytokines to investigate the effects of immunotherapies on patient survival. The model is first validated using the survival data of two clinical trials. Local sen- sitivity analysis of the parameters indicates there exists a critical activation rate of pro-tumor cytokines beyond which the cancer can be eradicated if four adoptive trans- fers of immune cells are applied. Optimal control theory is explored as a potential tool for searching the best adoptive cellular immunotherapies. Combined immunother- apies between adoptive ex vivo expanded immune cells and TGF-β inhibition by siRNA treatments are investigated. This study concludes that mono-immunotherapy is unlikely to control the pancreatic cancer and combined immunotherapies between anti-TGF-β and adoptive transfers of immune cells can prolong patient survival. We show through numerical explorations that how these two types of immunotherapies are scheduled is important to survival. Applying TGF-β inhibition first followed by adoptive immune cell transfers can yield better survival outcomes. This model is hosted on BioModels Database and identified by: MODEL1907050003. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Rhodes2019 - Immune-Mediated theory of Metastasis

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