processes
Article
Multiscale Agent-Based and Hybrid Modeling of the
Tumor Immune Microenvironment
Kerri-Ann Norton 1,2, * ,† , Chang Gong 1,† , Samira Jamalian 1,† and Aleksander S. Popel 1,3
1
Department of Biomedical Engineering, School of Medicine, Johns Hopkins University,
Baltimore, MD 21205, USA; cgong5@jhu.edu (C.G.); samira.jamalian@jhu.edu (S.J.)
2
Computer Science Program, Department of Science, Mathematics, and Computing, Bard College,
Annandale-on-Hudson, NY 12504, USA
3
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, School of Medicine,
Johns Hopkins University, Baltimore, MD 21205, USA; apopel@jhu.edu
* Correspondence: knorton@bard.edu; Tel.: +845-752-2307
† These authors contributed equally to this work.
Received: 11 December 2018; Accepted: 10 January 2019; Published: 13 January 2019
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.
Keywords: multiscale systems biology; computational biology; quantitative systems pharmacology
(QSP); immuno-oncology; immunotherapy; immune checkpoint inhibitor; mathematical modeling
1. Introduction
In recent years it has become increasingly evident that studying the tumor microenvironment
(TME), in addition to studying cancer cell transformation, is crucial to understanding tumor growth,
progression and dissemination. TME is a complex and heterogeneous milieu where cancer cells and
stromal cells (including immune cells and other cells resident in the tissue) interact with each other and
with the extracellular matrix (ECM), Figure 1. One of the critical elements of the TME is the tumor’s
interaction with the host immune system. Hanahan and Weinberg described evasion of the immune
system as one of the hallmarks of cancer [1]. The importance of the stromal microenvironment in tumor
progression was also recognized in the classical paper by Paget [2]. It has become clear that the tumor
stromal component, and specifically, the host immune system, contributes to tumor growth, and new
therapeutics are now being aimed at altering the immune system as a cancer target (see reviews [3,4]).
Processes 2019, 7, 37; doi:10.3390/pr7010037
www.mdpi.com/journal/processes
41
Article
Multiscale Agent-Based and Hybrid Modeling of the
Tumor Immune Microenvironment
Kerri-Ann Norton 1,2, * ,† , Chang Gong 1,† , Samira Jamalian 1,† and Aleksander S. Popel 1,3
1
Department of Biomedical Engineering, School of Medicine, Johns Hopkins University,
Baltimore, MD 21205, USA; cgong5@jhu.edu (C.G.); samira.jamalian@jhu.edu (S.J.)
2
Computer Science Program, Department of Science, Mathematics, and Computing, Bard College,
Annandale-on-Hudson, NY 12504, USA
3
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, School of Medicine,
Johns Hopkins University, Baltimore, MD 21205, USA; apopel@jhu.edu
* Correspondence: knorton@bard.edu; Tel.: +845-752-2307
† These authors contributed equally to this work.
Received: 11 December 2018; Accepted: 10 January 2019; Published: 13 January 2019
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.
Keywords: multiscale systems biology; computational biology; quantitative systems pharmacology
(QSP); immuno-oncology; immunotherapy; immune checkpoint inhibitor; mathematical modeling
1. Introduction
In recent years it has become increasingly evident that studying the tumor microenvironment
(TME), in addition to studying cancer cell transformation, is crucial to understanding tumor growth,
progression and dissemination. TME is a complex and heterogeneous milieu where cancer cells and
stromal cells (including immune cells and other cells resident in the tissue) interact with each other and
with the extracellular matrix (ECM), Figure 1. One of the critical elements of the TME is the tumor’s
interaction with the host immune system. Hanahan and Weinberg described evasion of the immune
system as one of the hallmarks of cancer [1]. The importance of the stromal microenvironment in tumor
progression was also recognized in the classical paper by Paget [2]. It has become clear that the tumor
stromal component, and specifically, the host immune system, contributes to tumor growth, and new
therapeutics are now being aimed at altering the immune system as a cancer target (see reviews [3,4]).
Processes 2019, 7, 37; doi:10.3390/pr7010037
www.mdpi.com/journal/processes
41