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

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

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Natural killer (NK) cells are innate cytotoxic lymphocytes that can recognize assorted determinants on tumor cells and rapidly kill these cells.Due LIQUID B COMPLEX 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 Batch Bowl Food Processors 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.