Manipulation of NK-cell immunity via metalloproteinases and chemokine receptor redirection in viral infection and cancer

Abstract

Natural killer cells perform their role of immunosurveillance and target killing by active engagement with ligands in the environment with their activating and inhibitory receptors, as well as their cytokine and chemokine receptors. It is well known that metalloproteinases can cleave ligands and chemokines to modify ligand-receptor interactions, chemotactic activity, and overall function. However, studies addressing how metalloproteinases manipulate these processes and how we can harness these to enhance natural killer cell activity in viral infection and cancer are lacking. Here, we discover the underlying mechanisms by which SARS-CoV-2 and related sarbecoviruses induce metalloproteinase-mediated cleavage of critical NK cells ligands, MIC-A/B, to evade natural killer cell immunity. We also probe the role of the metalloproteinase-cleaved chemokine CXCL16, which has demonstrated an increasingly important role in triple negative breast cancer. Lastly, as an extension of our work in probing chemokine-chemokine receptor axes, we set the groundwork to rewire NK-cell chemotaxis by introducing novel chemokine receptors as a therapeutic strategy to redirect them into tumor tissues and fully harness their cytotoxic potential.