Multiscale Agent-Based and Hybrid Modeling of the Tumor Immune Microenvironment

Abstract

Multiscale systems biology and systems pharmacology are powerful methodologies that are playing increasingly important roles in understanding the fundamental mechanisms of biological phenomena and in clinical applications. In this review, we summarize the state of the art in the applications of agent-based models (ABM) and hybrid modeling to the tumor immune microenvironment and cancer immune response, including immunotherapy. Heterogeneity is a hallmark of cancer; tumor heterogeneity at the molecular, cellular, and tissue scales is a major determinant of metastasis, drug resistance, and low response rate to molecular targeted therapies and immunotherapies. Agent-based modeling is an effective methodology to obtain and understand quantitative characteristics of these processes and to propose clinical solutions aimed at overcoming the current obstacles in cancer treatment. We review models focusing on intra-tumor heterogeneity, particularly on interactions between cancer cells and stromal cells, including immune cells, the role of tumor-associated vasculature in the immune response, immune-related tumor mechanobiology, and cancer immunotherapy. We discuss the role of digital pathology in parameterizing and validating spatial computational models and potential applications to therapeutics.

Computer Simulation Modeling for Analyzing Mammary Gland Tumor Cells Aggression Level Restricted by Comparative Chemotherapy using Docetaxel and Doxorubicin Both with Cyclophosphamide

“…Moreover, using agent-based modeling and simulation, it has been established by the community that the complex behavior of agents in complex systems is adaptive and autonomous (Wang et al, 2015;Macal, 2016;Hosseini and Naghavi, 2017;Jayasekera et al, 2018;Norton et al, 2019). The current study proves this concept practically by determining the agents of SMTA.…”

Special Issue: Methods in Computational Biology

“…Coverage includes not only a mathematical description, but also solvers and simulation considerations. Norton et al [2] provide a thorough review of agent-based modeling of tumor cells, tumor cell heterogeneity as well as tumor interactions with host immune system components and local physical environments.…”

“…Farzan and Ierapetritou [6] report on multicellular scale systems and analyze interactions between mammalian cells and the bioreactor environment with the ultimate goal of optimizing bioprocess applications. Norton et al [2] study systems on the cellular and tissue scales and examine the interactions between tumor cells, host immune cells and local microenvironments. Phalak and Henson [7] study a multicellular scale system quantifying the dynamic interactions between multiple microorganisms, including the exchange of metabolites, and the role of time and space on microbial infections.…”

Immunoactivating the tumor microenvironment enhances immunotherapy as predicted by integrative computational model

“…Given the complexity of the system with its multiscale nature and spatiotemporal dynamics, how can one integrate the knowledge of the interactions between the parts to understand the system response to therapeutics and make reliable predictions (e.g., for drug combinations, patient cohort selection, and drug regimens)? It is not possible without the advent of modern systems biology, specifically computational systems biology and quantitative systems pharmacology, which is being recognized as a necessary methodology in academia and pharmaceutical industry (14)(15)(16)(17). In PNAS, Mpekris et al (18) formulate an integrative computational model of tumor that includes multiple elements described above and explore the behavior of the system under different conditions.…”