UC San Diego

CD8+ T cells are the primary cytotoxic immune cells that are capable of directly killing cancer cells; however, their tumor-killing potential in solid tumors is often limited by insufficient infiltration into the tumor microenvironment. Recent findings suggest that the limited cytotoxic capacity of T cells is partly due to the increased stiffness of the extracellular matrix (ECM) that acts as a physical barrier. This barrier precludes direct T cell-cancer contact, a pre-requisite for contact-dependent killing. Despite this, the mechanisms by which ECM stiffness regulates T cell functions are not fully understood. Furthermore, recent findings demonstrate that tumors are not only stiff, but viscoelastic. Viscoelasticity is a mechanical property reflecting the time-dependent dissipation or relaxation of stresses within a material following deformation. However, the role of viscoelasticity in regulating CD8+ T cell migration remains poorly understood. To address this question, we developed collagen-alginate matrices with matched stiffness but distinct viscoelasticity to investigate how matrix viscoelasticity influences CD8+ T cell migration. Increasing viscoelasticity increased the mean cell volume of CD8+ T cells, decreased the migration straightness, and increased the proportion of the migration phenotype with moderate speed but higher speed standard deviation. The mechanosensitive ion channel inhibitor decreased cell migration speed and straightness in the low-viscoelasticity matrix but caused an opposite effect in the high-viscoelasticity matrix. Additionally, adding the ion channel inhibitor led to a higher proportion of inefficient migration subtype in the low-viscoelasticity matrix but not in the high-viscoelasticity matrix. These suggested that in tissues with lower viscoelasticity, normal mechanosensitive ion channel activity is important for CD8+ T cells to migrate efficiently. Together, these findings highlight the importance of matrix viscoelasticity and mechanosensitive ion channels in regulating CD8+ T cell migration and suggest that understanding and modulating migration phenotypes may provide new strategies to enhance T cell infiltration into solid tumors by engineering Piezo1 activity according to different tissue viscoelasticity.