Fluid shear stress enhances Natural Killer cell's cytotoxicity towards circulating tumor cells through NKG2D-mediated mechanosensing

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Abstract

Tumor cells metastasize to distant organs mainly via hematogenous dissemination, in which circulating tumor cells (CTCs) are relatively vulnerable and eliminating these cells has great potential to prevent metastasis. In vasculature, natural killer (NK) cells are the major effector lymphocytes for efficient killing of CTCs under fluid shear stress (FSS) that is an important mechanical cue in tumor metastasis. However, the influence of FSS on the cytotoxicity of NK cells against CTCs remains elusive. We report that the death rate of CTCs under both NK cells and FSS is much higher than the combined death induced by either NK cells or FSS, suggesting that FSS may enhance NK cell’s cytotoxicity. This death increment is elicited by shear-induced NK activation and granzyme B entry into target cells rather than the death ligand Trail or secreted cytokines TNF-α and IFN-γ. When NK cells form conjugates with CTCs or adhere to MICA-coated substrates, NK cell activating receptor NKG2D can directly sense FSS to induce NK activation and degranulation. These findings reveal the promotive effect of FSS on NK cell’s cytotoxicity towards CTCs, which thus provide new insights into immune surveillance of CTCs within circulation.
Original languageEnglish
JournalAPL Bioengineering
DOIs
Publication statusPublished - 11 Aug 2023

Keywords

  • Fluid shear stress
  • Mechanosensing
  • mechanotransduction
  • natural killer cell
  • circulating tumor cells

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