Poster L13 - OPTIMIZATION OF THERAPEUTIC T CELLS THROUGH BIOPHYSICAL MODELING

Introduction: Many solid tumors exhibit an immunologically cold tumor microenvironment, characterized by very limited distributions of cytotoxic T cells, thus limiting the success of cancer immunotherapies. Despite recent progress in understanding amoeboid-mesenchymal migratory balance, it remains largely unknown how T cells mechanically move through tumors and what factors set their migration capabilities. In this study, we aim to elucidate the physical principles and molecular components that modulate T cell migration capabilities, identify how these molecular regulators can be perturbed to enhance cell migration, and ultimately engineer and design therapeutic T cells to a cellular state of maximal tumor infiltration and migration.

Materials and

Methods: We are applying a novel approach, involving mathematical modeling, computer simulations, live cell imaging and genome engineering to push the frontiers of T cell migration. As a starting point, we have developed a biophysical T cell migration model [1]. The model considers the cell to be composed of two distinct structures: a cell membrane, modeled as an elastic structure subjected to interfacial forces, and an actomyosin cortex, modeled as a dynamic assembling-disassembling elastic structure that generates forces creating tension in the cortical network. Cortex and membrane are mechanically linked by reversible, force-sensitive membrane-cortex elastic linkers. The intracellular and extracellular media are assumed to be FENE-P viscoelastic materials with distinct mechanical properties, and their flow is modeled as incompressible and non-inertial. Osmotic effects are included, and momentum conservation is enforced. Biophysical model results are complemented by preliminary data obtained from in vitro T cell migration studies.

Results, Conclusions, and Discussions: We first examined the potential for adhesion-free bleb-based migration and show that cells only inefficiently migrate in the absence of adhesion-based forces, i.e., cell swimming. High-to-low cortical contractility oscillations, where a high cortical contractility phase characterized by multiple bleb nucleation events is followed by an intracellular pressure buildup recovery phase at low cortical tensions, results in modest net cell motion [1]. However, our model suggests that T cells can employ a hybrid bleb- and adhesion-based migration mechanism for rapid cell motility and identifies conditions for optimality [1].
The developed mathematical framework, driven by data on immune cell migration combined with key experiments suggested by model results, is helping us gain a new physical perspective of the mechanisms underlying single T cell migration, and bleb-based/amoeboid migration generally, that hopefully will change the way we design stroma targeting and engineered T cell therapies for enhanced T cell migration and associated tumor killing.
[1] Alonso-Matilla R, Provenzano PP., Odde DJ. bioRxiv. 2023.10.29.564655

Acknowledgements (Optional): The authors would like to thank the National Institutes of Health (grants U54CA210190, P01CA254849, and U54CA268069) for providing financial support to this project.