Tumour Immune Evasion is Promoted by Actin Cytoskeleton-Driven Polarization of Inhibitory Signals to the Immunological Synapse

Natural killer (NK) cells are innate immune cells that are the first line of defence against infection and malignant transformation. They have the ability to recognize and destroy virally infected or cancerous cells without the need for priming or activation and therefore represent a promising target for new immunotherapeutic approaches against cancer. For their anti-tumour function, NK cells rely on actin cytoskeleton remodelling, in particular during the formation of the lytic immunological synapse (IS) with prospective target cells. The IS is characterized by an extensive assembly of filamentous actin (F-actin) and polarization of the NK cell for directed delivery of lytic granules. However, the IS allows bi-directional exchange of information, and anti-tumour effector functions of NK cells are often impaired through inhibitory signals that are transmitted through killer immunoglobulin-like receptors (KIRs) or the CD94/NK group 2 member A (NKG2A) heterodimeric receptor. Moreover, resistant tumour cells can polarize their own actin cytoskeleton to the IS in a process called actin response, enforcing the formation of an evasion IS or actin response-IS (AR-IS).