Desarrollo de una plataforma de vacunación antitumoral basada en un ligando endógeno de moléculas TLR

• Autores: Lorea Villanueva Legarda
• Directores de la Tesis: Pablo Sarobe Ugarriza (dir. tes.)
• Lectura: En la Universidad de Navarra ( España ) en 2016
• Idioma: español
• Tribunal Calificador de la Tesis: L. Anel (presid.), Fernando Pastor Rodríguez (secret.), José Medina Echeverz (voc.), Cristina Latasa Osta (voc.), Sandra Hervás Stubbs (voc.)
• Programa de doctorado: Programa de Doctorado en Investigación Biomédica por la Universidad de Navarra
• Materias:
  • Ciencias de la vida
    • Inmunología
      • Inmunización
      • Vacunas
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• Resumen

  • Development of a new antitumor vaccination platform based on an endogenous ligand of TLR molecules Although antitumor therapeutic vaccination has not attained the expected results, new therapies based on checkpoint inhibiting antibodies suggest that the use of both strategies could yield results if properly combined. Our aim was thus to characterize a new vaccination platform based on an endogenous ligand of a receptor of the TLR family. In vitro, this TLR ligand (TL) induced dendritic-cell activation, migration and enhanced presentation of TL-bound antigens to T cells. Vaccination with TL-containing immunogens resulted in stronger T-cell responses, dependent on their immunostimulatory and antigen-targeting capacities, that when applied in a therapeutic setting led to rejection of an important proportion of tumors. Moreover, the efficacy of this vaccination platform was enhanced by combination with additional adjuvants or with antibodies blocking immunosuppressive molecules IL-10 and PD-L1 induced by the vaccine and present in the tumor enviroment. As a consequence, priming with TL-based vaccines combined with inhibitory antibodies rejected established B16-OVA tumors. Finally, equivalent activation and T-cell stimulatory effects were observed when using TL in vitro with human cells, suggesting that TL-based vaccination strategies could be a valuable clinical tool to include in combinatorial immunotherapeutic strategies in cancer patients.