SFB 1054 Seminar - Lukas Flatz
Title: Immunotherapy with propagating arenavirus-based vector breaks T cell tolerance to melanoma-associated antigens
Despite the success of targeted and immunotherapy, the development of novel approaches still remains a major goal in cancer therapy. Vaccine vectors based on arenaviruses, such as recombinant lymphocytic choriomeningitis virus (rLCMV) vectors, represent a potent therapeutic strategy to induce endogenous antitumor immunity. Here, we utilized two closely related generations of rLCMV vectors expressing the melanoma-associated self-antigen tyrosinase-related protein 2 (TRP2) to decipher the factors needed for inducing efficient antitumor immune responses. We demonstrate that both, the propagation-deficient r2LCMV and the propagation-attenuated r3LCMV vector transduce human and murine APCs. Unlike r2LCMV, vaccination with r3LCMV vectors resulted in prolonged antigen availability, strong activation of dendritic cells (DCs), and high levels of type I interferons (IFN-I) necessary for the generation of potent TRP2-specific T cell responses. Treatment with r3LCMV resulted in a decrease of regulatory T cells, thereby promoting the generation of TRP2-specific T cell responses. We further demonstrate that only vaccination with r3LCMV, but not with r2LCMV, results in a T cell-dependent growth inhibition of established melanomas. Our observations suggest that propagating r3LCMV vaccine vectors can overcome tolerance mechanisms to induce TRP2-specific anti-tumor T cell responses. Propagation competence of viral-based vectors may therefore be an important hallmark of a successful cancer vaccine targeting tumor-associated self-antigens.
Host: Dietmar Zehn (B14)