Acute myeloid leukaemia (AML) is an aggressive haematologic malignancy characterized by accumulation of immature myeloid cells in the bone marrow and peripheral blood, leading to failure of normal haematopoiesis. Despite recent approval of novel targeted therapies, the clinical outcome of patients remains poor, and relapse is still a common scenario, prompting the need for additional therapeutic approaches. The tumor microenvironment, that includes immune cells, orchestrates the survival and proliferation of leukaemic cells and drives therapy resistance. Evidence of disrupted immunoregulation in AML indicates immunotherapy as a promising therapeutic approach to improve patients’ outcome and obtain long-term disease control.

Many efforts have been made to redirect the immune system against leukaemic cells, but clinical success will depend on the ability of immunotherapy to target both the immunological dysregulated environment and the leukaemic cells that escape the immune system. This project, focusing on this major unmet need, will provide a systematic view of immune cells signatures found in AML, and a better understanding of the mechanisms behind leukaemic cells escaping strategies, using single cell multi-omics and patient derived organoids.

Single‐cell RNA sequencing will be used to unravel the composition of the immune environment in AML and identify clinically relevant immune cell subtypes implicated in immune evasion and chemotherapy resistance. Mass cytometry (CyTOF) will allow to track the phenotypic evolution of both immune cell types and leukaemia cells over time, identifying clinically relevant markers that may help targeting leukaemic cells that evade immune surveillance and promote disease progression. Validation of top targets will include immunotherapy response and toxicity studies in patient- derived organoids.