Activation of ADAM17 by IL-15 Limits Human NK Cell Proliferation

Front Immunol. 2021 Jul 22;12:711621. doi: 10.3389/fimmu.2021.711621. eCollection 2021.


Natural killer (NK) cells are innate cytotoxic lymphocytes that can recognize assorted determinants on tumor cells and rapidly kill these cells. Due to their anti-tumor effector functions and potential for allogeneic use, various NK cell platforms are being examined for adoptive cell therapies. However, their limited in vivo persistence is a current challenge. Cytokine-mediated activation of these cells is under extensive investigation and interleukin-15 (IL-15) is a particular focus since it drives their activation and proliferation. IL-15 efficacy though is limited in part by its induction of regulatory checkpoints. A disintegrin and metalloproteinase-17 (ADAM17) is broadly expressed by leukocytes, including NK cells, and it plays a central role in cleaving cell surface receptors, a process that regulates cell activation and cell-cell interactions. We report that ADAM17 blockade with a monoclonal antibody markedly increased human NK cell proliferation by IL-15 both in vitro and in a xenograft mouse model. Blocking ADAM17 resulted in a significant increase in surface levels of the homing receptor CD62L on proliferating NK cells. We show that NK cell proliferation in vivo by IL-15 and the augmentation of this process upon blocking ADAM17 are dependent on CD62L. Hence, our findings reveal for the first time that ADAM17 activation in NK cells by IL-15 limits their proliferation, presumably functioning as a feedback system, and that its substrate CD62L has a key role in this process in vivo. ADAM17 blockade in combination with IL-15 may provide a new approach to improve NK cell persistence and function in cancer patients.

Keywords: ADAM17 (a disintegrin and metalloprotease 17); CD62L; IL-15; natural killer cell; proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / antagonists & inhibitors
  • ADAM17 Protein / immunology
  • ADAM17 Protein / metabolism*
  • Adoptive Transfer
  • Animals
  • Cell Division
  • Enzyme Activation
  • Female
  • Heterografts
  • Humans
  • Interleukin-15 / metabolism
  • Interleukin-15 / pharmacology*
  • Killer Cells, Natural / cytology*
  • Killer Cells, Natural / enzymology
  • L-Selectin / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Receptors, Cell Surface / metabolism
  • Recombinant Proteins / pharmacology


  • IL15 protein, human
  • Interleukin-15
  • Receptors, Cell Surface
  • Recombinant Proteins
  • SELL protein, human
  • L-Selectin
  • ADAM17 Protein
  • ADAM17 protein, human