Immunere programmining response to antiangiogenic-mediahteydp oxia in breast cancer

• Autores: Jose Luis Ruiz Sepúlveda
• Directores de la Tesis: Miguel Angel Quintela Fandiño (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2023
• Idioma: inglés
• Número de páginas: 112
• Títulos paralelos:
  • Reprogramación inmune en respuesta a la hipoxia generada por agentes antiangiogénicos en cáncer de mama
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Immunotherapy has significantly improved outcome for some aggressive cancers, but the benefit is still limited to certain subsets of patients and tumor types. Combination treatments may be the key to extend the benefit of immunotherapy to more patients and for longer duration. Antiangiogenic agents might be one of such treatments, as they can promote vascular normalization and enhance the inflammatory context in the tumors. In CNIO-BR-008 clinical trial we demonstrated that Bevacizumab and Durvalumab combination show a modest benefit in the subset of patients that develop vascular normalization, while those which developed a high hypoxic adaption to anti-angiogenic treatment, were unable to benefit from anti-PD-L1 In this project, we investigated the immune adaptation that occurs in the high hypoxic microenvironment after anti-VEGF-A treatment with the aim to understand the drivers of PD-L1 resistance and capitalize the findings in new therapeutic options. Anti-VEGF-A treatment was able to extend the survival of MMTV-PyMT breast mouse models by reducing tumor growth, but also hypoxia arose in part of the mice promoting lack of benefit from anti-PD-L1 combination in comparation with the low hypoxic ones. We found two levels of resistance in this system. First, in high hypoxic conditions, a myeloid derived inflammation was found to be strongly activated by tumor-associated macrophages. When macrophages were depleted from tumors by combining anti-CSF1R treatment with anti-VEGFA there was a reduction in tumor growth and any subject was able to develop a high hypoxic resistance. Macrophages produced different compensatory pro-angiogenic factors, promoting vascular instability and high hypoxia leading to the generation of hypoxic resistance. Osteopontin, a cytokine produced by tumor cells, shall be crucial in the attraction of macrophages in the tumor and the acquisition of pro-angiogenic phenotypes. Indeed, blocking osteopontin in vivo was improving the outcome of mice by promoting low hypoxic responses. The second level of resistance may be related with the response to immunotherapy combinations depending on different patterns of hypoxic adaptation. When high hypoxia is stablished, cytotoxic T cells are reduced in the tumor microenvironment while immunosuppressive Treg and M2-macrophages are being accumulated, with higher production of tolerogenic cytokines and reducing the capacity of T cell co-stimulation. These contributed to a deep exhausted phenotype in cytotoxic T cells that made them unable to respond to anti-PD-L1 therapy. However, anti-CTLA-4 inhibited Treg functions and boosted T cell co-stimulation process, being able to recover anti-tumoral function and extending survival in mice on both low and high hypoxic conditions. Finally, combining adding anti-osteopontin to anti-PD-L1 and anti-VEGF-A was able to recover the response to anti-PD-L1 by preventing the hypoxic resistance to anti-angiogenic treatment. In conclusion, we have found that high hypoxic resistance to anti-VEGF-A promoted a strong immunosuppressive tumor microenvironment that hinders benefit from anti-PD-L1, but antiCTLA-4 is able recovering anti-tumor immune function even in these conditions. This resistance was being promoted by the release of osteopontin from tumor cells, which cause the attraction and activation of macrophages in pro-angiogenic phenotypes. Therefore, the blockade of macrophage infiltration or osteopontin clearance was able to prevent the hypoxic adaptation to anti-VEGFA. These findings could be attractive approaches that could be further studied to extend to clinical trials in the future