title: In vivo evidence that secretion of HLA-G by immunogenic tumor cells allows their evasion from immunosurveillance.
abstract: Human leukocyte antigen-G (HLA-G) expression by tumors has been evidenced in numerous malignancies in association with poor prognosis and resistance to immunotherapy in humans. Particularly, soluble form of HLA-G was measured at high concentrations in malignant effusions and plasma from cancer patients, and inhibits antitumor immune cells in vitro through interaction with immunoglobulin-like transcript (ILT) receptors. Nevertheless, in vivo study demonstrating that HLA-G secretion by tumor cells allows their escape from immunosurveillance remained to be established. Despite nondescribed murine homolog, direct functional interaction of HLA-G with murine paired immunoglobulin-like receptor (PIR)-B, ortholog of human ILT receptors, enables to investigate its role in vivo. Immunocompetent mice were injected either with syngeneic tumor cells co-expressing HLA-G5, the main soluble HLA-G isoform, and the conformation stabilizer human β2-microglubulin (hβ2m), or with hβ2m+ HLA-G5- tumor cells. hβ2m expressed at both tumor cell surface acted as a tumor antigen triggering a specific humoral response. Interestingly, although hβ2m+ HLA-G5- tumors were rejected, secreted HLA-G5 provided hβ2m+ HLA-G5+ tumors a protection against hβ2m-elicited immune rejection, enabling such immunogenic tumors to grow similarly to a poorly immunogenic tumor. HLA-G5 tumor expression was associated with local and peripheral immunosuppression, characterized by dampened anti-hβ2m B-cell response, quantitative and functional T-and B-cell defects, accumulation of myeloid-derived suppressor cells able to inhibit T-cell proliferation and reduced T- and B-cell tumor infiltrate. Our study provides the first in vivo proof that soluble HLA-G counteracts tumor rejection and reinforces the importance to consider HLA-G as a promising target to optimize current cancer immunotherapies.
authors.affiliation: CEA, IMETI, Service de Recherches en Hemato-Immunologie (SRHI), Hopital Saint-Louis, Paris, France; Institut Universitaire d'Hematologie (IUH), Hopital Saint-Louis, UMR_E5, Universite Paris-Diderot-Paris-7, Paris, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Loumagne
authors.forename: Jeremy
authors.initials: J
authors.lastname: Baudhuin
authors.forename: Benoit
authors.initials: B
authors.lastname: Favier
authors.forename: Florent
authors.initials: F
authors.lastname: Montespan
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouas-Freiss
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D059951:HLA-G Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015166:Monitoring, Immunologic; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D059951:HLA-G Antigens
keywords: HLA-G; immunotolerance; myeloid-derived suppressor cells; tumor escape