Abstract
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.
Highlights
Natural killer (NK) cells interrogate cells in the body for infection and transformation and eliminate these cells by rapidly induced effector activities, including a potent cytolytic process [1]
We show that A disintegrin and metalloproteinase-17 (ADAM17) activity regulates IL-15-mediated NK cell proliferation in vitro and in vivo, and that the homing receptor CD62L is a substrate involved in this process
We have previously reported that IL-15 stimulation of human NK cells activates ADAM17 in short-term experiments (≤ 24 hours) [23]
Summary
NK cells interrogate cells in the body for infection and transformation and eliminate these cells by rapidly induced effector activities, including a potent cytolytic process [1]. Human peripheral blood NK cells are identified as CD56+ CD3−, and their effector activities are ADAM17 Regulates NK Cell Proliferation rapidly induced by numerous germline-encoded receptors that respond to ligands upregulated and downregulated on tumor cells as well as attached antibodies [1]. In consideration of this and their potential for allogeneic use, various NK cell platforms are being evaluated for adoptive cell therapies to treat hematologic malignancies and solid tumors [4, 5]. Challenges for IL-15 immunotherapy, include the inhibitory actions of immunological checkpoints that it induces, and there is a considerable emphasis on identifying new mechanisms of action that improve the functionality of IL-15 therapy in cancer patients [13]
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