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Killer Dendritic Cells Link Innate and Adaptive Immunity against Established Osteosarcoma in Rats

¹ Institut National de la Sante et de la Recherche Medicale, U643; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, IUN; and Université de Nantes, Faculté de Médecine; ² Institut National de la Sante et de la Recherche Medicale, ERI 7, and Université de Nantes, Faculté de Médecine, EA 3822-Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives; and ³ CHU de Nantes, Laboratoire d'Immunologie, Nantes, France

Requests for reprints: Françoise Rédini, EA 3822-Institut National de la Sante et de la Recherche Medicale ERI7, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France. E-mail: francoise.redini{at}univ-nantes.fr or Régis Josien, Institut National de la Sante et de la Recherche Medicale U643-ITERT, 30 Boulevard Jean Monnet, 44093 Nantes Cedex 1, France. Phone: 33-240-087-413; Fax: 33-240-087-411; E-mail: Regis.Josien{at}univ-nantes.fr.

Key Words: dendritic cells • cytotoxicity • osteosarcoma

We have previously reported that a distinct subset of splenic CD4^– rat dendritic cells (DC) induces a rapid and caspase-independent apoptosis-like cell death in a large number of tumor cells in vitro. The killing activity of these killer DC (KDC) was restricted to their immature state and was immediately followed by their engulfment of the apoptotic target cells, suggesting that these KDC could directly link innate and adaptive immunity to tumors. Here, we addressed this question using a transplantable model of rat osteosarcoma. First, we showed that rat KDC have an MHC II⁺CD103⁺CD11b⁺NKp46^– phenotype and are therefore distinct from natural killer cells, which are MHC II^–CD103^–CD11b^–NKp46⁺. KDC numbers could be specifically and strongly (up to 10-fold) enhanced by Flt3L in vivo. The OSRGa cell line derived from the osteosarcoma tumor was killed and phagocytosed in vitro by both normal and Flt3L-induced splenic KDC. Such tumor antigen–loaded KDC were used to s.c. vaccinate progressive tumor-bearing rats. Vaccination with OSRGa-loaded KDC but not KDC loaded with irrelevant tumor cells (Jurkat) delayed tumor progression or even induced tumor regression. This vaccine effect was not observed in CD8 T cell–depleted animals and protective against tumor rechallenge. These results suggest that KDC possess the intrinsic capability not only to kill and then engulf tumor cells but also to efficiently cross-present tumor cell–derived antigen in vivo and subsequently induce an adaptive antitumor immune response. [Cancer Res 2008;68(22):9433–40]