2025 GIGA Annual Report | 35 Grégory Ehx Laboratory of Hematology Acute myeloid leukemia (AML) is the most frequent and lethal leukemia among adults. Although chemotherapy results in high rates of remission, most patients relapse, leading to average survival rates of ~10-40%. Relapse is notably mediated by leukemic cells (persisters) surviving chemotherapy, and remaining dormant throughout the remission phase. Because these cells are vastly outnumbered by T cells (the effectors of antileukemic immunity) during remission, targeting them with immunotherapies is a golden opportunity to prevent AML relapse. However, blasts can escape immune recognition through various mechanisms, notably through the expression of immune checkpoint molecules (ICMs). Therefore, our study aims to design immunotherapies targeting persisters by stimulating their T-cell recognition through vaccination and by inhibiting the ICMs protecting them. Recently, we designed a proteogenomic method enabling the detection of MHC-I-presented antigens specifically expressed by AML blasts (TSA) which could serve as vaccination targets. Here, we will use this approach to identify the TSAs presented by persisters generated by treating patient-derived AML cells with chemotherapy. To identify key ICMs protecting persisters, we will perform a large-scale molecular screening in vitro, and more detailed analyses in immunodeficient mice co-transplanted with primary AML blasts and T cells, or without T cells. Through singlecell RNA sequencing, we will track persisters in the bone marrow of AML patients and characterize the evolution of their ICM+TSA expression profile to prioritize the most desirable immunotherapeutic targets. Finally, we will test our immunotherapeutic strategy in a preclinical model of AML in humanized mice. Our study could help prevent AML relapse and could elucidate the immune escape mechanisms of AML cells following chemotherapy. GRÉGORY EHX IMMUNOERADICATION OF PERSISTER CELLS IN AML
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