PERSTIM

Hematological malignancies such as acute myeloid leukemia (AML) and multiple myeloma (MM) arise, reside and evolve in the bone marrow niche. A better understanding of the factors of persistence of tumor cells and the interactions with the tumor microenvironment (TME) is of utmost importance. In recent years, improvements in the treatment of hematological malignancies, notably targeted therapies and new generations immunotherapies, have led to deep and prolonged responses. However, patients still ultimately relapse. This is particularly true in both AML and MM, which are associated with poor clinical outcomes, despite the fact that patients often reach negative minimal residual disease (MRD) after initial treatment. This suggests that rare malignant cells are able to persist within the bone marrow niche and induce disease relapse. Two main factors dictate whether a patient will respond or not to a given treatment. Firstly, factors largely tumor-dependent, such as the clonal evolution and plasticity of malignant cells, escaping the treatment efficacy and inducing the emergence of resistant sub-clones at relapse. Secondly, the immune system is largely patient- and tumor-dependent, capable of recognizing and subsequently acting on the immunogenicity of the tumor. Notably, tumors accumulate mutations over time leading to the generation of neoantigens. In addition, these neoantigens have to be presented in an immunogenic rather than in an immunosuppressive environment for an effective antitumor immune response to occur. In our team project, we combine single cell genomics, transcriptomics, multiplex tissue immunophenotyping and functional assays to investigate how the different components of the marrow environment counteract or support clonal evolution and plasticity of malignant cells under different modalities of leukemia/myeloma treatments. The ultimate goal is to identify novel strategies to modulate dysfunctional interactions and improve durable tumor remission.