Unexpected modulation of T cell activity by mechanical cues

Abstract

Abstract Current immunotherapies take advantage of the biochemical features of T cell activation and function, such as strengthening the antigenic responses of T cells. However, the biophysical properties and the physical environment of T cells are also relevant. Using polyacrylamide (PAA) gels to vary the mechanical landscape, we show that the mechanical environment of T cells dictates T cell capacity. Mechanical properties of PAA gels include viscoelasticity, porosity, and stiffness. Using a robotic platform that enables the automatic collection of cytokines from T cells co-cultured with tumors of varying antigenic strengths, we show that not only does antigenic quality influence T cell function, but altering the crosslinking of the PAA gel, and thus the physical environment, results in varied T cell response. Low crosslinking impairs T cell function, while increasing crosslinking gradually improves response. By using other hydrogels, we ruled out stiffness as a mediator of T cell response. Rheology and atomic force microscopy (AFM) will help uncover the physical characteristics that dictate response. Modeling these properties is essential in identifying the mechanical landscape responsible for immune response and predicting this response based on the tumor physical environment. These findings will introduce a novel approach to treating cancer by assessing the mechanical properties of the tumor and changing the physical environment to one that allows for a favorable immune response.