Abstract
Chronic lymphatic leukemia (CLL) and follicular lymphoma (FL) are among the most prevalent hematological malignancies, but remain incurable despite recent therapeutic advances. They are defined by a progressive expansion of mature clonal B cells. A striking feature of both diseases is their strong dependence on microenvironmental interactions that promote the survival and immune escape of malignant B cells. Remarkably, B-cell clones with typical features of CLL and FL are frequently found in asymptomatic individuals, but the factors that control progression of these premalignant clones to overt CLL or FL remain unknown. We propose a novel hypothesis whereby aberrant crosstalk between conventional dendritic cells (cDCs) and T cells underlies clonal progression of premalignant B cells, and constitutes a shared pathogenic mechanism in CLL and FL. In this project, we aim to provide a comprehensive overview of the cellular and molecular interactions in the immune environment at different stages of disease, using a single-cell and spatial transcriptomics approach. We will apply computational methods to identify alterations in T cells and/ or cDCs that drive disease progression, and validate key findings through ex vivo assays of T cell and cDC function and using innovative in vivo mouse models of CLL and FL. A better understanding of the immune alterations in these patients may benefit the development of novel immunotherapeutic approaches.
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