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

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.

NK Cell Regulation in Cervical Cancer and Strategies for Immunotherapy

“…On the other hand, Pham et al showed that the treatment of NK cells with the ADAM17 inhibitor (TAPI-1) increases the purity of NK cells expanded ex vivo, the expression of CD16 (FcγRIII), IFN-γ production and improves antibody-dependent cytotoxicity activity against breast cancer cells. These data do not indicate that blocking ADAMs proteases may have a dual role and provide a new approach enhancing the persistence and function of NK cells in cancer patients [82][83][84][85][86][87][88][89][90].…”

The Omentum in Obesity-Associated Cancer: A Hindrance to Effective Natural Killer Cell Migration towards Tumour Which Can Be Overcome by CX3CR1 Antagonism

“…Interestingly, whilst IL-15 significantly increased the frequencies of cells expressing L-selectin and α4β7, simultaneous exposure to fractalkine undermines these effects, suggesting that fractalkine antagonises the stimulatory effects of IL-15 in relation to enhanced adhesion molecule expression. Previous work has shown short term stimulation with IL-15 increases L-selectin expression on NK cells, while a recent report has shown longer term stimulation can decrease L-selectin expression which can stifle NK cell expansion [ 45 , 46 ].…”

Natural Killer Cells in the Malignant Niche of Multiple Myeloma

“…Another candidate is ADAM17, which is activated through the IL-15 axis and reduces NK cell proliferation. Blockade of this metalloproteinase results in increased levels of L-selectin (CD62L) on NK cells, thus supporting the homing of these cells (176). However, not only downregulation of the IL-15R function, but also chronic exposure to IL-15 leads to the NK cell exhaustion (177).…”