Study of immune resistant mechanisms in mouse models of breast cancer

• Autores: Pilar Baldominos Flores
• Directores de la Tesis: Rafael Sirera Pérez (dir. tes.), Judith Agudo Cantero (dir. tes.)
• Lectura: En la Universitat Politècnica de València ( España ) en 2024
• Idioma: inglés
• Tribunal Calificador de la Tesis: Stefanie K. Wculek (presid.), Miriam Sanso Martinez (secret.), Julio Aguirre-Ghiso (voc.)
• Programa de doctorado: Programa de Doctorado en Biotecnología por la Universitat Politècnica de València
• Materias:
  • Ciencias de la vida
    • Biología celular
    • Inmunología
    • Biología molecular
  • Ciencias médicas
    • Ciencias clínicas
      • Oncología
• Enlaces
  • Tesis en acceso abierto en: RiuNet
• Resumen

  • Immunotherapy is a promising treatment for Triple-Negative Breast Cancer (TNBC), but many patients relapse or do not respond, highlighting the need to understand mechanisms of resistance. In this doctoral thesis we discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. These Quiescent Cancer Cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell-RNA-sequencing with precise spatial resolution to profile infiltrating cells (stromal and immune cells) inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified the presence of more abundant exhausted T-cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location with respect to QCCs. We were also able to identify HIF1a expression in QCC as the driver of immune exclusion and dysfunction. Forced activation of a HIF1a program in cancer cells recapitulated the immune phenotype observed in the QCCs' niche. Thus, QCCs constitute immunotherapyresistant reservoirs by orchestrating a local immune-suppressive milieu that blocks DC activation impairing T-cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.