American Association for Cancer Research
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Supplementary Materials and Methods from Metalloprotease-Mediated Tumor Cell Shedding of B7-H6, the Ligand of the Natural Killer Cell–Activating Receptor NKp30

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posted on 2023-03-30, 22:08 authored by Eva Schlecker, Nathalie Fiegler, Annette Arnold, Peter Altevogt, Stefan Rose-John, Gerhard Moldenhauer, Antje Sucker, Annette Paschen, Elke Pogge von Strandmann, Sonja Textor, Adelheid Cerwenka

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Natural killer (NK) cells are potent immune effector cells capable of mediating antitumor responses. Thus, during immunoediting, tumor cell populations evolve strategies to escape NK-cell–mediated recognition. In this study, we report a novel mechanism of immune escape involving tumor cell shedding of B7-H6, a ligand for the activating receptor NKp30 that mediates NK-cell binding and NK-cell–mediated killing. Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases “a disintegrin and metalloproteases” (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells. Notably, we documented elevated levels of soluble B7-H6 levels in blood sera obtained from a subset of patients with malignant melanoma, compared with healthy control individuals, along with evidence of elevated B7-H6 expression in melanoma specimens in situ. Taken together, our results illustrated a novel mechanism of immune escape in which tumor cells impede NK-mediated recognition by metalloprotease-mediated shedding of B7-H6. One implication of our findings is that therapeutic inhibition of specific metalloproteases may help support NK-cell–based cancer therapy. Cancer Res; 74(13); 3429–40. ©2014 AACR.

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