Interferon-g and Tumor Necrosis Factor-a Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE77814 | GEO | 2017/02/09
SECONDARY ACCESSION(S): PRJNA311612
REPOSITORIES: GEO
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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.
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This model is described in the article:
Modeling anti-tumor Th1 and Th2 immunity in the rejection of melanoma
Raluca Eftimie, Jonathan L. Bramson, David J.D. Earn
Journal of Theoretical Biology 265 (2010) 467–480
Abstract:
Recent experiments indicate that CD4+ Th2 cells can reject skin tumors in mice, while CD4+ Th1 cells cannot (Mattes et al., 2003; Zhang et al., 2009). These results are surprising because CD4+ Th1 cells are typically considered to be capable of tumor rejection. We used mathematical models to investigate this unexpected outcome. We found that neither CD4+ Th1 nor CD4+ Th2 cells could eliminate the cancer cells when acting alone, but that tumor elimination could be induced by recruitment of eosinophils by the Th2 cells. These recruited eosinophils had unexpected indirect effects on the decay rate of type 2 cytokines and the rate at which Th2 cells are inactivated through interactions with cancer cells. Strikingly, the presence of eosinophils impacted tumor growth more significantly than the release of tumor-suppressing cytokines such as IFN-g and TNF-a. Our simulations suggest that novel strategies to enhance eosinophil recruitment into skin tumors may improve cancer immunotherapies.
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