National Institute of Health and Medical Research (INSERM)
Project Term: July 1, 2019 - June 30, 2022
This proposal will explain how follicular lymphoma (FL) arises from normal B-cell activation. Using the first mouse models that reflect the true biology of FL integrated with sophisticated analyzes of primary human FL, we will define the nature and evolution of the FL tumor microenvironment in relationship with the main FL-specific genetic alterations and identify key therapeutic vulnerabilities that will lead to a new class of precision-targeted therapy for this otherwise incurable tumor.
Follicular lymphoma (FL) is the most common indolent lymphoma, remains essentially incurable, and is thus a major public health concern in western countries. FL arises as the immortalization of B cells found within the germinal center (GC), the place of activation and selection of cells producing antibodies with high affinity for pathogens. The minimal genetic hallmark of FL involves: i) deregulation of the survival gene BCL2 and ii) mutations of genes involved in the regulation of expression and activity of other genes, i.e. epigenetic regulators. FL development relies on both the accumulation of such genetic alterations inside tumor B cells and the dynamic bidirectional interactions between malignant B cells and specific subsets of non-malignant GC cells, in particular CD4pos T cells and stromal cells, forming a tumor supportive niche favoring B-cell survival and growth. A main issue in this disease is how to target the crosstalk between B cells and their microenvironment through innovative therapeutic approaches. Our preliminary data, based on our original mouse models mimicking FL disease and on the analysis of FL patient samples, have revealed that i) mutations in epigenetic genes, namely EZH2, KMT2D, and CREBBP, are associated with aberrant regulation of molecules supposed to be involved in the interaction between malignant B cells and their immune microenvironment; ii) other recurrent genetic alterations, targeting HVEM or immunoglobulin genes, could directly impact FL B-cell niche. Collectively, these data suggested that each genetic alteration could be more generally associated with the progressive organization of a specific niche variably involving microenvironment cell subsets and signaling pathways. Taking advantage of our development of the first animal models that faithfully reproduce the stepwise progression of FL and our sets of primary human FL specimens we will define at serial time-points how the various genetic alterations commonly found in FL could specifically reprogram the GC microenvironment to generate a FL permissive cell niche. We will use novel therapeutic agents that disrupt the crosstalk between FL-specific microenvironment and lymphoma cells as the basis to develop the first precision epigenetic microenvironment targeted therapy approaches with the goal of translating these regimens to the clinic by the end of the study period.