MICA triggering signal for NK cell tumor lysis is counteracted by HLA-G1-mediated inhibitory signal.
MICA, a highly glycosylated membrane-anchored cell-surface MHC Class I-related chain, has recently been reported to activate NK cell cytolytic responses in epithelial tumors. Tumor cells may escape from NK lysis by counteracting NK cytotoxicity activating signals with inhibitory ones. Among the molecules that mediate an NK inhibitory signal, HLA-G1, a non-classical MHC Class I antigen, is of particular interest. HLA-G1 is ectopically expressed in various tumors, including melanoma and constitutes the major NK inhibitory ligand in the M8 melanoma cell line when coexpressed with HLA-A, -B, -C and -E molecules. We have evaluated the balance between 2 powerful signals that affect NK cell tumor lysis, one inhibitory and the other one activating, respectively HLA-G1 and MICA. For this purpose, we transfected the M8 melanoma cell line, which spontaneously expresses MICA, with HLA-G1 cDNA, using it as a target for the NKL effector. We carried out cytotoxicity assays, using antibodies that disrupt interactions between the MICA and HLA-G1 ligands and their respective NK effector counterparts, the NKG2D activating and ILT2 inhibitory receptors. Results showed that 1) MICA expressed in the M8 melanoma cell line triggered NK cell tumor lysis and 2) HLA-G1 coexpression mediated the inhibition of NK cytotoxicity by mitigating the MICA activating signal. HLA-G1 expression in a tumor cell line in which MICA is switched on would therefore appear to be a powerful way to turn off NK cells, supporting the emerging idea that the balance between positive and negative NK cytolysis signals critically influences tumor progression.
Service de Recherche en Hémato-Immunologie, Direction des Sciences du Vivant, Département de Recherche Médicale, Commissariat à l'Energie Atomique, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France.
Catherine
C
Menier
Béatrice
B
Riteau
Edgardo D
ED
Carosella
Nathalie
N
Rouas-Freiss
D000818:Animals; D000911:Antibodies, Monoclonal; D019921:Biotinylation; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006680:HLA Antigens / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007163:Immunosorbent Techniques; D007694:Killer Cells, Natural / Q000276:immunology*; D008545:Melanoma / Q000737:chemistry / Q000276:immunology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D010920:Placenta / Q000737:chemistry / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D015398:Signal Transduction; D014162:Transfection; D014327:Trophoblasts / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D008565:Membrane Proteins