Dendritic cells break tolerance and induce protective immunity against a melanocyte differentiation antigen in an autologous melanoma model

Tyrosinase-related protein (TRP) 2 belongs to the melanocyte differentiatio n antigens and has been implicated as a target for immunotherapy of human a s well as murine: melanoma, In the current report, we explored the efficacy of nonmutated epitopes with differential binding affinity for MHC class I, derived from mouse TRP2 to induce CTL-mediated, tumor-reactive immunity in vivo within the established B16 melanoma model of C57BL/6 mice. The use of nonmutated TRP2-derived epitopes for vaccination provides a mouse model th at closely mimics human melanoma without introduction of xenogeneic or othe rwise foreign antigen. The results demonstrate that vaccination with TRP2 p eptide-loaded bone marrow-derived dendritic cells (DCs) results in activati on of high avidity TRP2-specific CTLs, displaying lytic activity against bo th B16 melanoma cells and normal melanocytes in vitro. In vivo, protective antitumor immunity against a lethal s.c, B16 challenge was observed upon DC -based vaccination in this fully autologous tumor model. The level of prote ctive immunity positively correlated with the MHC class I binding capacity of the peptides used for vaccination. In contrast, within this autologous m odel, vaccination with TRP2 peptide in Freund's adjuvant or TRP2-encoding p lasmid DNA did not result in protective immunity against B16, Strikingly, d espite the observed CTL-mediated melanocyte destruction in vitro, melanocyt e destruction in vivo was sporadic and primarily restricted to minor depigm entation of the vaccination site. These results emphasize the potency of DC -based vaccines to induce immunity against autologous tumor-associated anti gen and indicate that CTL-mediated antitumor immunity can proceed without d evelopment of adverse autoimmunity against normal tissue.