Natural Killer cell contractility and cytotoxicity is driven by TLR3 agonist-mediated TAZ cytoplasmic sequestration

Abstract

The evolutionarily conserved YAP/TAZ mechano-responsive transcription cofactors regulate development and tumorigenesis. Here, we show for the first time that human natural killer (NK) cells specifically express TAZ but not YAP, and TAZ serves to limit NK cytotoxicity. The TLR3 agonist, hiltonol, was able to trigger cytoplasmic sequestration of TAZ, which increased NK cytotoxicity. Mechanistically, a low dose of hiltonol enhanced the intracellular contractility of NK cells accompanied by an increase in active RhoA and myosin light chain phosphorylation, conceivably through an increase in ERK1/2 activation-dependent ROS production. Importantly, we showed that the dissociation of LATS1 from actin upon activation of contractility, is required to sequester TAZ in the cytoplasm. Functionally, hiltonol also reduced the NK cell surface inhibitory receptors, KIR3DL1 through c-Myc inhibition and PD-1 through enhanced contractility. Direct inhibition of c-Myc promoted NK cytotoxicity against K562 lymphoblast. We corroborated our findings by coculturing hiltonol-pretreated NK cells with breast and lung cancer cells, and demonstrated increased NK-mediated cancer killing, which conceivably occurred via sequestration of TAZ to the cytoplasm which facilitated NK cytotoxicity. Our findings pave the way for ex vivo rejuvenation of NK cells for in vivo immunotherapies, which could involve a cocktail of hiltonol and c-Myc inhibitor.

Liposomes-Encapsulating Double-Stranded Nucleic Acid (Poly I:C) for Head and Neck Cancer Treatment

“…HNSCC is a common malignancy that often presents with locoregional disease and can spread to distant sites . Recent studies have shown that HNSCC cells express elevated levels of Toll-like receptor-3 (TLR-3), which is involved in the recognition of viral RNA and the activation of antitumor immunity. − TLR3 is one of 10 members of the TLR family, which contains an extracellular domain that recognizes and binds to pathogen-associated molecular patterns and also a cytoplasmic tail which acts as residual for recruitment of TLR3 signal mediators. ,, …”