Tumor-induced natural killer cell dysfunction is a rapid and reversible process uncoupled from the expression of immune checkpoints

Sci Adv. 2024 Aug 30;10(35):eadn0164. doi: 10.1126/sciadv.adn0164. Epub 2024 Aug 28.

Abstract

Natural killer (NK) cells often become dysfunctional during tumor progression, but the molecular mechanisms underlying this phenotype remain unclear. To explore this phenomenon, we set up mouse lymphoma models activating or not activating NK cells. Both tumor types elicited type I interferon production, leading to the expression of a T cell exhaustion-like signature in NK cells, which included immune checkpoint proteins (ICPs). However, NK cell dysfunction occurred exclusively in the tumor model that triggered NK cell activation. Moreover, ICP-positive NK cells demonstrated heightened reactivity compared to negative ones. Furthermore, the onset of NK cell dysfunction was swift and temporally dissociated from ICPs induction, which occurred as a later event during tumor growth. Last, NK cell responsiveness was restored when stimulation was discontinued, and interleukin-15 had a positive impact on this reversion. Therefore, our data demonstrate that the reactivity of NK cells is dynamically controlled and that NK cell dysfunction is a reversible process uncoupled from the expression of ICPs.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Immune Checkpoint Proteins / genetics
  • Immune Checkpoint Proteins / metabolism
  • Interleukin-15 / metabolism
  • Killer Cells, Natural* / immunology
  • Killer Cells, Natural* / metabolism
  • Lymphocyte Activation / immunology
  • Lymphoma / immunology
  • Lymphoma / pathology
  • Mice
  • Mice, Inbred C57BL

Substances

  • Immune Checkpoint Proteins
  • Interleukin-15