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Endogenous Retrovirus Expression Is Required for Murine Melanoma Tumor Growth In vivo

Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, Unité Mixte de Recherche 8122, Centre National de la Recherche Scientifique, Institut Gustave Roussy, Villejuif, France

Requests for reprints: Thierry Heidmann, Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, Unité Mixte de Recherche 8122, Centre National de la Recherche Scientifique, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. Phone: 33-1-42-11-49-70; Fax: 33-1-42-11-53-42; E-mail: heidmann{at}igr.fr.

Tumor development is a multistep process in which both genetic and epigenetic events cooperate for the emergence of a malignant clone. The possibility that endogenous retroviruses promote the expansion of a neoplastic clone by subverting immune surveillance has been proposed, but remained elusive. Here we show that knocking down—by RNA interference—an endogenous retrovirus spontaneously induced in the B16 murine melanoma results in the rejection of the tumor cells in immunocompetent mice, under conditions where control melanoma cells grow into lethal tumors. The knockdown does not modify the transformed phenotype of the cells, as measured both in vitro by a soft agar assay and in vivo by tumor cell proliferation in immunoincompetent (X-irradiated and severe combined immunodeficiency) mice. Tumor rejection can be reverted upon adoptive transfer of regulatory T cells from control melanoma-engrafted mice, as well as upon reexpression of the sole envelope gene of the endogenous retrovirus in the knocked down cells. These results show that endogenous retroviruses can be essential for a regulatory T-cell–mediated subversion of immune surveillance and could be relevant to human tumors where such elements—and especially their envelope gene—are induced.

Key Words: Endogenous Retrovirus • Tumor • Melanoma • Regulatory T Cells • RNAi

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