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

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.

Macrophages in Oral Carcinomas: Relationship with Cancer Stem Cell Markers and PD-L1 Expression

“…Nusblat et al [ 34 ] showed that in the presence of conditioned media from M2 macrophages, CSCs increased migration and collagen degradation capacities. In addition, CSCs may exert a strong immune suppressive effect by suppressing the Major Histocompatibility Complex (MHC) by macrophages in the TME, releasing the exosomal miRNAs miR-9 and miR-21, or by secreting VEGF that plays a pivotal role in tumor angiogenesis and suppression of T-cell maturation [ 35 ]. Mazzoldi et al [ 36 ] found that, the c-Kit ligand Stem Cell Factor (SCF), produced by M2 macrophages, may favor the immune escape of tumor cells in ovarian cancer.…”

Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma

“…Though a plethora of models exist on the basis of the assumption that proliferation of a constant fraction of tumor volume follows exponential growth but in this model we have considered the widely accepted and well-known model of Gomphertz to describe growth dynamics of cancer cells and their heterogeneous subpopulations ( 33 , 34 ). Mathematical representation of growth kinetics followed by cancer cells can be given as α C *C , where K denotes carrying capacity of the cancerous cells ( 35 ).…”

From Chaos to Opportunity: Decoding Cancer Heterogeneity for Enhanced Treatment Strategies

“…For instance, the existence of diverse fractions of slow-cycling cells, commonly known as “quiescent” cancer cells, within the tumor mass can impede the effectiveness of immune checkpoint inhibitors [ 58 ]. Additionally, cancer heterogeneity can also encompass the variability in the recruitment of distinct populations of immune and immuno-regulatory cells within the TME [ 59 ]. The composition of the TME, including the presence of immune-suppressive cells such as regulatory T cells and myeloid-derived suppressor cells, can further impact the response to immunotherapy [ 60 , 61 ].…”