Thesis Paula Martinez Sanz

Abstract

Neutrophils are known to have opposing roles in a cancer setting. Depending on the circumstances they can either promote tumor progression via immunosuppressive mechanisms, or eliminate cancer cells when triggered by an antigen-targeting antibody via antibody-dependent cellular cytotoxicity. In the present thesis we highlight different ways in which the neutrophil’s anti-tumor functions can be harnessed in immunotherapeutic strategies to improve cancer treatment. We showed how stimulating the neutrophils with G-CSF or GM-CSF cytokines enhances the antibody-mediated killing capacity of neutrophils towards anti-GD2-opsonized neuroblastoma cells, in particular. We also found that the strategic disruption of SIRPα/CD47 axis in combination with anti-GD2 antibody improved the neutrophil’s cytotoxic capacities in this cancer type even further, just as found for other cancer subtypes. Additionally, we demonstrated how the innovative approach of genetically modifying neutrophil-like cells to express CAR constructs effectively redirected the neutrophil’s cytotoxic functions towards their respective solid tumor targets, offering an alternative therapeutic strategy that obviates the need of exogenous therapeutic antibodies. Last, to advance in the preclinical study of human neutrophils in vivo, we further characterized the phenotype and functionality of such neutrophils in the humanized MISTRG mouse strain. We confirmed that this next-generation in vivo model can be used as a model system for the preclinical evaluation and study of neutrophil-mediated immunotherapeutic strategies.