Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30.
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.
Authors' Affiliations: Innate Immunity and.
Eva
E
Schlecker
Authors' Affiliations: Innate Immunity and.
Nathalie
N
Fiegler
Authors' Affiliations: Innate Immunity and.
Annette
A
Arnold
Translational Immunology, Department of Tumor Immunology, German Cancer Research Center, Heidelberg;
Peter
P
Altevogt
Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel;
Stefan
S
Rose-John
Translational Immunology, Department of Tumor Immunology, German Cancer Research Center, Heidelberg;
Gerhard
G
Moldenhauer
Department of Dermatology, University Hospital, University Duisburg-Essen, Essen; and.
Antje
A
Sucker
Department of Dermatology, University Hospital, University Duisburg-Essen, Essen; and.
Annette
A
Paschen
Department of Internal Medicine I, Centre for Integrated Oncology Koeln Bonn, University of Cologne, Cologne, Germany.
Elke Pogge
EP
von Strandmann
Authors' Affiliations: Innate Immunity and s.textor@dkfz.de.
Sonja
S
Textor
Authors' Affiliations: Innate Immunity and.
Adelheid
A
Cerwenka
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D060887:B7 Antigens / Q000097:blood / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D061986:MCF-7 Cells; D008545:Melanoma / Q000097:blood / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000276:immunology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D013876:Thiophenes / Q000494:pharmacology; D019139:Tumor Escape; D015854:Up-Regulation / Q000187:drug effects
C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide; D060887:B7 Antigens; D004151:Dipeptides; D006877:Hydroxamic Acids; D008565:Membrane Proteins; C431710:NCR3 protein, human; C542363:NCR3LG1 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3; D011480:Protease Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; C100342:marimastat; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human