Dataset Information

Ganguli2018-immuno regulatory mechanisms in tumor microenvironment

ABSTRACT: This model describes the concept of Cancer Stem Cells(CSC) differentiation and tumor-immune interaction into a generic model that has been validated with known experimental data. Created by COPASI 4.24(Build197) Abstract: The tumor microenvironment comprising of the immune cells and cytokines acts as the 'soil' that nourishes a developing tumor. Lack of a comprehensive study of the interactions of this tumor microenvironment with the heterogeneous sub-population of tumor cells that arise from the differentiation of Cancer Stem Cells (CSC), i.e. the 'seed', has limited our understanding of the development of drug resistance and treatment failures in Cancer. Based on this seed and soil hypothesis, for the very first time, we have captured the concept of CSC differentiation and tumor-immune interaction into a generic model that has been validated with known experimental data. Using this model we report that as the CSC differentiation shifts from symmetric to asymmetric pattern, resistant cancer cells start accumulating in the tumor that makes it refractory to therapeutic interventions. Model analyses unveiled the presence of feedback loops that establish the dual role of M2 macrophages in regulating tumor proliferation. The study further revealed oscillations in the tumor sub-populations in the presence of TH1 derived IFN-γ that eliminates CSC; and the role of IL10 feedback in the regulation of TH1/TH2 ratio. These analyses expose important observations that are indicative of Cancer prognosis. Further, the model has been used for testing known treatment protocols to explore the reasons of failure of conventional treatment strategies and propose an improvised protocol that shows promising results in suppressing the proliferation of all the cellular sub-populations of the tumor and restoring a healthy TH1/TH2 ratio that assures better Cancer remission.

DISEASE(S): Breast Cancer,Cancer

SUBMITTER: Szeyi Ng

PROVIDER: BIOMD0000000810 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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	BIOMD0000000810?filename=Ganguli2018-immuno%20regulatory%20mechanisms%20in%20tumor%20microenvironment-biopax2.owl	Owl
	BIOMD0000000810?filename=Ganguli2018-immuno%20regulatory%20mechanisms%20in%20tumor%20microenvironment-biopax3.owl	Owl
	BIOMD0000000810?filename=Ganguli2018-immuno%20regulatory%20mechanisms%20in%20tumor%20microenvironment-matlab.m	Other
	BIOMD0000000810?filename=Ganguli2018-immuno%20regulatory%20mechanisms%20in%20tumor%20microenvironment-octave.m	Other
	BIOMD0000000810?filename=Ganguli2018-immuno%20regulatory%20mechanisms%20in%20tumor%20microenvironment.cps	Other

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Publications

Exploring immuno-regulatory mechanisms in the tumor microenvironment: Model and design of protocols for cancer remission.

Ganguli Piyali P Sarkar Ram Rup RR

PloS one 20180905 9

The tumor microenvironment comprising of the immune cells and cytokines acts as the 'soil' that nourishes a developing tumor. Lack of a comprehensive study of the interactions of this tumor microenvironment with the heterogeneous sub-population of tumor cells that arise from the differentiation of Cancer Stem Cells (CSC), i.e. the 'seed', has limited our understanding of the development of drug resistance and treatment failures in Cancer. Based on this seed and soil hypothesis, for the very firs ...[more]

PMID: 30183728

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Project description:Cryo-thermal therapy has been proven to be a promising novel systemic strategy for advanced breast cancer, resulting in higher incidence of tumor regression and enhanced remission of metastasis. The mechanism by which such strategy boosts the anti-tumor activity remains unclear. To gain a system-wide understanding of the anti-tumor response, here we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare the N-glycoproteome changes following treatment or not in 94 serum samples over 8 time points. We quantified 231 high confident N-glycosylated serum proteins in total using iTRAQ labeling shotgun proteomic. 53 of them showed significant regulatory patterns over time course, in which we identified acute phase response as the most enhanced pathway and markedly distinguished in the hierarchical proteome profile. We therefore investigated the function of acute response in tumoricidal effect using quantitative parallel reaction monitoring proteomics and flow cytometry upon 23 out of 53 significant proteins. We found that cryo-thermal therapy reshaped the tumor chronic inflammatory microenvironment to an ‘acute’ phenotype, accompanying ‘acute’ and markedly high expression of acute phase proteins and their key upstream regulator -interleukin 6. Such IL-6 mediated ‘acute’ phenotype drove the tumor site from a Th2 immunosuppressive, pro-tumorigenic to a Th1 immunostimulatory, tumouricidal phenotype, inducing a switch from IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN –γand IL-12 production, skewing to complement system activation and CD86+MHCII+ dendritic cells maturation, and enhancing the proliferation of Th1 memory cells. We also found an increased production of tumor metastatic inhibitors under such ‘acute’ environment, favoring the anti-metastatic effect. In this study, we revealed that IL-6 mediated ‘acute’ inflammatory profile played a key role to suppress immunosuppression and wake up the anti-tumor activity, recovering host metabolism and physiology. This could guide us a better understanding to improve this cancer treatment for better therapeutic effect.

Project description:The paper describes a model of interaction of Th cells and macrophage in melanoma. Created by COPASI 4.25 (Build 207) This model is described in the article: Modelling and investigation of the CD4 T cells – Macrophages paradox in melanoma immunotherapies Raluca Eftimie, Haneen Hamam Journal of Theoretical Biology 420 (2017) 82–104 Abstract: It is generally accepted that tumour cells can be eliminated by M1 anti-tumour macrophages and CD8+ T cells. However, experimental results over the past 10–15 years have shown that B16 mouse melanoma cells can be eliminated by the CD4+ T cells alone (either Th1 or Th2 sub-types), in the absence of CD8+ T cells. In some studies, elimination of B16 melanoma was associated with a Th1 immune response (i.e., elimination occurred in the presence of cytokines produced by Th1 cells), while in other studies melanoma elimination was associated with a Th2 immune response (i.e., elimination occurred in the presence of cytokines produced by Th2 cells). Moreover, macrophages have been shown to be present inside the tumours, during both Th1 and Th2 immune responses. To investigate the possible biological mechanisms behind these apparently contradictory results, we develop a class of mathematical models for the dynamics of Th1 and Th2 cells, and M1 and M2 macrophages in the presence/absence of tumour cells. Using this mathematical model, we show that depending on the re- polarisation rates between M1 and M2 macrophages, we obtain tumour elimination in the presence of a type-I immune response (i.e., more Th1 and M1 cells, compared to the Th2 and M2 cells), or in the presence of a type- II immune response (i.e., more Th2 and M2 cells). Moreover, tumour elimination is also possible in the presence of a mixed type-I/type-II immune response. Tumour growth always occurs in the presence of a type-II immune response, as observed experimentally. Finally, tumour dormancy is the result of a delicate balance between the pro-tumour effects of M2 cells and the anti-tumour effects of M1 and Th1 cells. 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.