TALETE

Background, rationale
Survival of Acute Myeloid Leukemia (AML) is poor. To improve patients’ outcomes, immunotherapy is a promising strategy. The causative role of immunosuppressive bone marrow (BM) microenvironment, where overexpression of immune checkpoint (IC) receptors, such as PD-1 and tryptophan degradation via indoleamine 2,3-dioxygenase (IDO)1 mediate immune-tolerance, is emerging. However, an early translation of IDO1 and IC inhibitors in AML has provided modest clinical results.
Hypothesis
IDO-1-based microenvironment mechanisms of resistance hamper AML immunotherapy
Aims
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 microenvironment to resistance mechanisms
3. To functionally validate ex-vivo data by in vitro modeling
Methods
BM samples will be collected from a cohort of AML patients prospectively enrolled in Phase 1-2 immunotherapy clinical trial with Azacitidine, anti-IDO1 (Epacadostat), and anti-PD1 (INCMGA00012). 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 resistance and the identification of biomarkers associated with response 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.