Modeling immune cell behavior across scales in cancer

Advanced Review

Sahak Z. Makaryan, Colin G. Cess, Stacey D. Finley

Published Online: Mar 04 2020

DOI: 10.1002/wsbm.1484

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Abstract Detailed, mechanistic models of immune cell behavior across multiple scales in the context of cancer provide clinically relevant insights needed to understand existing immunotherapies and develop more optimal treatment strategies. We highlight mechanistic models of immune cells and their ability to become activated and promote tumor cell killing. These models capture various aspects of immune cells: (a) single‐cell behavior by predicting the dynamics of intracellular signaling networks in individual immune cells, (b) multicellular interactions between tumor and immune cells, and (c) multiscale dynamics across space and different levels of biological organization. Computational modeling is shown to provide detailed quantitative insight into immune cell behavior and immunotherapeutic strategies. However, there are gaps in the literature, and we suggest areas where additional modeling efforts should be focused to more prominently impact our understanding of the complexities of the immune system in the context of cancer. This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Models of Systems Properties and Processes > Cellular Models

Schematic of natural killer (NK) cell signaling and activation. NK cells express a repertoire of stimulatory and inhibitory receptors. Engagement of the NK cell surface receptors to ligands presented by tumor cells initiates intracellular signaling, including cascades of phosphorylation reactions. In addition, intracellular signaling can be promoted by antibodies that bind to tumor cell receptors and increase engagement of NK cells and tumor cells, termed antibody‐dependent cell‐mediated cytotoxicity (ADCC). The intracellular signaling enables the NK cells to become activated, leading to secretion of cytokines such as IL‐2 and IFN γ, as well as degranulation of granzyme B and perforin. Overall, NK cell activation mediates tumor cell killing. GRZ b: granzyme B; Gray arrows: activating interaction; Red bars: inhibiting interaction

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Computational models in cancer encompass multiple aspects of immune cell behavior. Multiscale models can account for spatial effects and represent the whole body. Multicellular models include immune and cancer cells to represent the tumor microenvironment. Models of single cells focus on intracellular signaling networks. AKT, ERK, and PLCγ are intracellular signaling species that mediate immune cell activation

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Schematic of interactions between tumor cells and different immune cell populations. Tumor and immune cells interact in various ways: certain immune cells impede tumor cell proliferation and survival, whereas others lead to a pro‐tumor environment by directly targeting tumor cells or inhibiting activation of other immune cells. Gray arrows: activating interaction; Red bars: inhibiting interaction; Dashed line: macrophage polarization

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