Enhanced and sustained T cell activation in response to fluid shear stress

Abstract

The efficacy of Tcell therapies in treating solid tumors is limited by poor invivo persistence, proliferation, and cytotoxicity, which can be attributed to limited and variable exvivo activation. Herein, we present a 10-day kinetic profile of Tcells subjected to fluid shear stress (FSS) exvivo, with and without stimulation utilizing bead-conjugated anti-CD3/CD28 antibodies. We demonstrate that mechanical stimulation via FSS combined with bead-bound anti-CD3/CD28 antibodies yields a synergistic effect, resulting in amplified and sustained downstream signaling (NF-κB, c-Fos, and NFAT), expression of activation markers (CD69 and CD25), proliferation and production of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2). This study represents the first characterization of the dynamic response of primary Tcells to FSS. Collectively, our findings underscore the critical role of mechanosensitive ion channel-mediated mechanobiological signaling in Tcell activation and fitness, enabling the development of strategies to address the current challenges associated with poor immunotherapy outcomes.