Enhancing T Cell Migration through Structurally and Mechanically Complex Tumor Microenvironments

Monday, April 6, 2020 - 3:40pm - 4:20pm
Rec Center - Beacon Rm
Paolo Provenzano (University of Minnesota, Twin Cities)
Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding sanctuaries from antitumor immunity and optimizing T cell-related therapeutic strategies. To enhance cytotoxic T cell migration through complex microenvironments, we engineered nanotextured platforms that allowed us to define how the balance between T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues and characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubules instability, leading to increased cell contractility, promotes migration while clinically used microtubule-targeting chemotherapies profoundly decrease effective migration. Indeed, we show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and sample the tumor volume, suggesting an effective strategy to enhance immune therapeutics.