Wiskott-Aldrich Syndrome Protein as a cytoskeletal mechanosensor driving the Natural Killer Cell Response

Immune cells receive and integrate information according to their micro-environmental cues to coordinate local and systemic behavior. Microenvironments provide active and passive mechanical cues that elicit biochemical signals through mechanotransduction. This interaction is crucial for understanding how tumor cells escape NK cell immune surveillance and how they render the NK cells dysfunctional. Recent studies demonstrated the role of mechanotransduction in modulating NK cell responses in the TME. The immunological synapse represents a functional interface between the NK cell and its target, regulated by Actin Retrograde Flow (ARF), driving the adhesion molecules and receptors toward the central zone of the immunological synapse (IS). Here, we further characterize the role of ARF in controlling the immune response of NK cells in a Wiskott-Aldrich Syndrome protein (WASp) mediated fashion. We demonstrate that WASp regulates ARF velocity, affecting the conformation and function of the key NK inhibitory regulator, SH2-domain containing protein tyrosine phosphatase-1 (SHP-1), and consequently determining NK cell response. Our results demonstrate the potential of modulating the biophysical and intracellular regulation of NK activation as a promising approach for improving immunotherapy.