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

PLoS One. 2018 Sep 5;13(9):e0203030. doi: 10.1371/journal.pone.0203030. eCollection 2018.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Cytokines / metabolism
  • Disease Progression
  • Drug Resistance, Neoplasm / immunology
  • Humans
  • Macrophages / immunology
  • Models, Immunological*
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Neoplastic Stem Cells / immunology
  • Remission Induction
  • Tumor Microenvironment / immunology*


  • Cytokines

Grants and funding

We thank SERB, Department of Science and technology, Govt. of India (file no. EMR/2016/000516), for providing financial support to Ram Rup Sarkar. Piyali Ganguli acknowledges Council of Scientific & Industrial Research (CSIR) for the Junior Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.