Evaluation of innate and adaptive immune system interactions in the tumor microenvironment via a 3D continuum model

Abstract

Immune cells in the tumor microenvironment (TME) are known to affect tumor growth, vascularization, and extracellular matrix (ECM) deposition. Marked interest in system-scale analysis of immune species interactions within the TME has encouraged progress in modeling tumor-immune interactions in silico. Due to the computational cost of simulating these intricate interactions, models have typically been constrained to representing a limited number of immune species. To expand the capability for system-scale analysis, this study develops a three-dimensional continuum mixture model of tumor-immune interactions to simulate multiple immune species in the TME. Building upon a recent distributed computing implementation that enables efficient solution of such mixture models, major immune species including monocytes, macrophages, natural killer cells, dendritic cells, neutrophils, myeloid-derived suppressor cells (MDSC), cytotoxic, helper, regulatory T-cells, and effector and regulatory B-cells and their interactions are represented in this novel implementation. Immune species extravasate from blood vasculature, undergo chemotaxis toward regions of high chemokine concentration, and influence the TME in proportion to locally defined levels of stimulation. The immune species contribute to the production of angiogenic and tumor growth factors, promotion of myofibroblast deposition of ECM, upregulation of angiogenesis, and elimination of living and dead tumor species. The results show that this modeling approach offers the capability for quantitative insight into the modulation of tumor growth by diverse immune-tumor interactions and immune-driven TME effects. In particular, MDSC-mediated effects on tumor-associated immune species' activation levels, volume fraction, and influence on the TME are explored. Longer term, linking of the model parameters to particular patient tumor information could simulate cancer-specific immune responses and move toward a more comprehensive evaluation of immunotherapeutic strategies.

Keywords: 3D continuum model; Adaptive immune system; Innate immune system; Mixture model; Tumor microenvironment; Tumor model.