Frontiers in Pharmacology (May 2022)

An in silico Model of T Cell Infiltration Dynamics Based on an Advanced in vitro System to Enhance Preclinical Decision Making in Cancer Immunotherapy

  • Thomas D. Lewin,
  • Blandine Avignon,
  • Alessio Tovaglieri,
  • Lauriane Cabon,
  • Nikolche Gjorevski,
  • Lucy G. Hutchinson

DOI
https://doi.org/10.3389/fphar.2022.837261
Journal volume & issue
Vol. 13

Abstract

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Cancer immunotherapy often involves the use of engineered molecules to selectively bind and activate T cells located within tumour tissue. Fundamental to the success of such treatments is the presence or recruitment of T cells localised within the tumour microenvironment. Advanced organ-on-a-chip systems provide an in vitro setting in which to investigate how novel molecules influence the spatiotemporal dynamics of T cell infiltration into tissue, both in the context of anti-tumour efficacy and off-tumour toxicity. While highly promising, the complexity of these systems is such that mathematical modelling plays a crucial role in the quantitative evaluation of experimental results and maximising the mechanistic insight derived. We develop a mechanistic, mathematical model of a novel microphysiological in vitro platform that recapitulates T cell infiltration into epithelial tissue, which may be normal or transformed. The mathematical model describes the spatiotemporal dynamics of infiltrating T cells in response to chemotactic cytokine signalling. We integrate the model with dynamic imaging data to optimise key model parameters. The mathematical model demonstrates a good fit to the observed experimental data and accurately describes the distribution of infiltrating T cells. This model is designed to complement the in vitro system; with the potential to elucidate complex biological mechanisms, including the mode of action of novel therapies and the drivers of safety events, and, ultimately, improve the efficacy-safety profile of T cell-targeted cancer immunotherapies.

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