Abstract
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.
Highlights
Natural killer (NK)-cell activation is determined by a delicate balance of signals received via inhibitory and activating receptors [1,2,3]
Because matrix metalloproteases (MMP) and a disintegrin and metalloproteases" (ADAM) play an important role in proteolytic shedding of cell surface molecules from tumor cells such as NKG2D ligands [18,19,20], we investigated the effect of metalloprotease inhibitors on the release of B7-H6 from tumor cells
Our study demonstrates that tumor cells release B7-H6, the ligand for the activating NK-cell receptor NKp30, by ectodomain shedding, leading to decreased surface levels of B7-H6 on tumor cells and reduced NKp30-mediated recognition by NK cells
Summary
Natural killer (NK)-cell activation is determined by a delicate balance of signals received via inhibitory and activating receptors [1,2,3]. Inhibitory receptors mainly recognize self-MHC class I molecules. Activating receptors, such as natural cytotoxicity receptors (NCR), or NKG2D, interact with virus-, stress-, transformation-, or senescence-inducible ligands [1, 4, 5]. These ligands are normally not expressed on the cell surface of healthy cells. Tumor cells frequently express high levels of activating NK-cell receptor ligands and low levels of Authors' Affiliations: 1Innate Immunity and 2Translational Immunology, Department of Tumor Immunology, German Cancer Research Center, Heidelberg; 3Department of Biochemistry, Christian-Albrechts-Universita€t zu Kiel, Kiel; 4Department of Dermatology, University Hospital, University Duisburg-Essen, Essen; and 5Department of Internal Medicine I, Centre for Integrated Oncology Koeln Bonn, University of Cologne, Cologne, Germany.
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