title: Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases.
abstract: The growth of immunogenic tumors in immunocompetent individuals is one of the oldest conundrums in tumor immunology. Although the ability of mouse CD8+ T cells to control transplanted tumors is well documented, little is known about their impact on autochthonous tumors. To gain insight into the role of CD8+ T cells during the course of cancer development, we produced a novel model of spontaneous melanoma. The metallothionein (MT)-ret/AAD mouse is transgenic for the RET oncogene and the chimeric MHC molecule AAD (alpha1-alpha2 domains of HLA-A2 linked to alpha3 domain of H2-Dd). This model recapitulates the natural history of human melanoma, and expression of the AAD molecule makes it suitable for analyzing CD8+ T cell responses directed against peptide Ags that have been previously identified in HLA-A2+ melanoma patients. We found that, as tumors grow, mice develop a broad melanoma-specific CD8+ T cell response. Occurrence of cutaneous nodules is not affected by CD8+ T cell depletion, showing that although CD8+ T cells are functional, they have no effect on established cutaneous tumors. However, depleted mice die from visceral disease much earlier than controls, showing that CD8+ T cells control metastasis spreading and disease progression. Antigenic modulation is observed in visceral metastases, suggesting that visceral nodules may be subject to immunoediting. Our data demonstrate that growth of melanoma in the MT-ret/AAD model involves several tolerance mechanisms sequentially. They also reveal a different role for CD8+ T cells toward early stage of cutaneous tumors and late visceral metastatic stage of the disease.
authors: Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.
authors: Renée
authors: R
authors: Lengagne
authors: Stéphanie
authors: S
authors: Graff-Dubois
authors: Marylène
authors: M
authors: Garcette
authors: Laurent
authors: L
authors: Renia
authors: Masashi
authors: M
authors: Kato
authors: Jean-Gérard
authors: JG
authors: Guillet
authors: Victor H
authors: VH
authors: Engelhard
authors: Marie-Françoise
authors: MF
authors: Avril
authors: Jean-Pierre
authors: JP
authors: Abastado
authors: Armelle
authors: A
authors: Prévost-Blondel
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006680:HLA Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D008212:Lymphocyte Depletion; D008545:Melanoma / Q000276:immunology* / Q000556:secondary; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape; D014781:Viscera / Q000473:pathology
chemical_list: D006680:HLA Antigens; D015789:HLA-A2 Antigen; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human