Investigate the Impact of Viscoelasticity on γδ T Cell Migratory Behaviors for Enhanced Tumor Infiltration

Abstract

Adoptive T cell therapies are an emerging area of immunotherapy that have shown promise in treating cancer, especially blood-based tumors and melanomas. Yet, their efficacy in solid tumors remains limited. Most studies have primarily used alpha beta (αβ) T cells which are restricted by MHC class presentation. This allows some tumors to evade immune detection. Recent attention has shifted toward gamma delta (γδ) T cells, a small but functionally significant subset of T cells that bridge innate and adaptive immunity. Their MHC-independent antigen recognition and cytotoxic response capabilities position them as promising candidates for adoptive immunotherapies. While 𝛾𝛿 T cells have been used in a variety of clinical trials globally, 𝛾𝛿 T cells still have limited efficacy in attacking solid tumors, primarily due to low tissue migration and residency. Emerging research suggests that mechanical cues in the microenvironment can influence T cell phenotype and function. In this paper, we hypothesize that mechanical modulation of the culture environment can promote a more tissue-adapted γδ T cell state. Using a collagen type I hydrogel platform with independently tunable stiffness and viscoelasticity, we encapsulated γδ T cells and assessed phenotype and motility by flow cytometry and time‑lapse imaging. We found that viscoelastic, fast‑relaxing hydrogels enhance γδ T‑cell migration, as evidenced by increased mean squared displacement and average speed over time. In parallel, we observe increased expression of the activation and stress-associated receptors PD1 and NKG2D. These results suggest that engineering the mechanical properties of the cell culture environment can modulate γδ T‑cell migratory and activation states with implications for improving their efficacy in solid tumor immunotherapy.