title: Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17.
abstract: The expression of HLA-G by malignant cells has been proposed as a tumor escape mechanism from immunosurveillance. However, although the inhibitory effect of HLA-G on antitumoral immune effectors has been documented in vitro, it remains to be resolved in vivo. In this context, the development of an animal model is now a priority to establish the proof of concept that an HLA-G(+) tumor cell develops and tolerizes the host antitumor immune response in vivo. In the present study, we provide the first in vivo evidence of such a role by a xenotumor model in mice based on the interactions between human HLA-G and the murine paired immunoglobulin-like receptor-B (PIR-B). We demonstrate that human tumor cells expressing HLA-G grow in an immunocompetent host by affecting both innate and adaptive immunity. Expansion of blood myeloid-derived CD11b(+)Gr1(+)PIR-B(+) suppressor cells, loss of peripheral T cells, and cytokinic balance in favor of Th2 versus Th1/Th17 constitute the main mechanisms by which HLA-G promotes tumor expansion. These data demonstrate for the first time that HLA-G plays a crucial role in in vivo tumor evasion. Finally, blocking HLA-G function by a specific Ab inhibits the in vivo development of the tumor, offering a new innovative therapeutic strategy in cancer.
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut d'Imagerie BioMédicale, Service de Recherches en Hémato-Immunologie, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Agaugué
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouas-Freiss
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D015166:Monitoring, Immunologic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D058408:Th1-Th2 Balance; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D019139:Tumor Escape
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C105949:Pirb protein, mouse; D020033:Protein Isoforms; D011971:Receptors, Immunologic