Interrogating resistance mechanisms to PD-1 blockade therapy

• Autores: Davis Yuri Torrejon Castro
• Directores de la Tesis: Antoni Ribas (dir. tes.), Joan Carles Galcerán (codir. tes.), Joan Seoane Suarez (codir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2021
• Idioma: inglés
• Tribunal Calificador de la Tesis: Albert Selva O'Callaghan (presid.), Ignacio Javier Melero Bermejo (secret.), Daniel E. Speiser (voc.)
• Programa de doctorado: Programa de Doctorado en Medicina por la Universidad Autónoma de Barcelona
• Materias:
  • Ciencias médicas
    • Ciencias clínicas
      • Oncología
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Immunotherapy with PD-1 or PD-L1 blockade has been proved to accomplish long term anti-tumor responses in patients with metastatic cancer, but it is extremely important to understand why some patients never respond to this mode of therapy, and how some patients respond and then progress. We have been studying resistance mechanisms to PD-1 blockade in patient biopsies and human melanoma cell lines mediated by JAK1/2 loss-of-function mutations in the IFN-receptor pathway and the inactivation of B2M in the antigen presentation.

    To characterize the biological significance and validate the role of these mutations leading to resistance to PD-1 blockade, we developed genetic acquired resistant models of JAK1, JAK2 and B2M loss-of-function mutations by gene knockout in human melanoma cell lines and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to interferon IFN-induced antitumor effects, while B2M knockout were no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy in vivo.

    Based on the mechanistic understanding of these genetic acquired resistance mutations, we allowed the design of strategies aimed to overcome resistance. JAK1/2 knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. B2M knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy.