TArgeting acute myeloid Leukemia immunosuppressive microEnvironment by combined IDO1 inhibiTion and PD-1 blockadE
Survival of Acute Myeloid Leukemia (AML) is poor. To improve patients’ outcomes, immunotherapies have the potential to circumvent some of the mechanisms leading to treatment failure, but their exploitation against AML has been unsatisfactory. The major reason for that relies on the largely incomplete understanding of the interactions between leukemia and immune cells in AML microenvironment. In that, the causative role of immunosuppressive bone marrow (BM) pathways, including overexpression of immune checkpoint (IC) receptors, such as PD-1 and tryptophan degradation via indoleamine 2,3- dioxygenase (IDO)1 is not fully elucidated.
IDO-1-based microenvironment mechanisms of resistance hamper AML immunotherapy
To explore TRANSCAN-3 AIM1, the following objectives will be addressed: 1. To decipher the composition of the BM microenvironment 2. To unravel the contribution of the immune microenvironment in response to azacitidine and venetoclax 3. To functionally validate ex-vivo data by in vitro modeling
Methods BM samples will be collected from a cohort of AML patients receiving the combination of azactidine and venetoclax, which represents the backbone for innovative therapeutic strategies in AML through the addition of novel compounds, such as immunomodulatory drugs. The project activities will be structured in 4 interconnected and integrated work packages. WP1: Project Management, Ethics, Dissemination, and Training, capacity building activity. WP2: Characterization of BM microenvironment: mass cytometry, single-cell RNA-seq, immunometabolism, and epigenetics (multi-omics). WP3: Experimental in vitro modeling to validate mechanisms of resistance (co-cultures, cell interactions). WP4: Methodology, Biostatistics, and Bioinformatics: integrated analysis of clinical and multi-omics data.
Expected results and potential impact
The expected discovery of microenvironment-based mechanisms of susceptibility to immunotherapies will affect clinical practice by improving patients’ selection. The expected development of a novel platform for BM microenvironment investigation will impact technology transfer by providing advanced diagnostic tools
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.