Project 2 : Functional heterogeneity of follicular lymphoma tumor microenvironment

Elise Dessauge (engineer); Baptiste Brauge (PhD student); Marion Guirriec (engineer); Simon Léonard, PhD (engineer); Cédric Ménard, PharmD PhD (assistant professor); Frédéric Mourcin, PhD (CR EFS)

FL development from normal GC B cells involves as genetic hallmarks: i) the founder

t(14;18) translocation associated with the deregulation of BCL2; ii) somatic mutations in histone modifier genes including KMT2D/MLL2, EZH2, and CREBBP. Of particular interest, some of the most frequent genetic hits in FL favor interactions with surrounding pro-tumoral non-B cells. In particular, inactivation of HVEM triggers a similar Tfh activation profile in both VavP-BCL2 FL mouse models and in FL patients (Boice, Salloul, Mourcin Cell 2016), suggesting that adequate genetically-engineered mouse models (GEMM) could be useful to decipher FL microenvironment subversion.

Importantly, besides the functional description of the dynamic FL tumor niche network, a major unsolved question remains the identification of the molecular mechanisms driving FL-microenvironment differentiation and polarization. FL stromal cells play a central role in FL pathogenesis through the direct activation of FL B cells, the indirect organization of the lymphoma-permissive cell niche, and probably the contribution to FL immune escape. Another key lymphoma-driver cell subset is Tfh. In particular, FL Tfh-derived IL-4 have been implicated in malignant B cell growth but also myeloid and stromal cell activation (Ame-Thomas Leukemia 2012; Amin Blood 2015; Pandey Blood 2017). The dynamic crosstalk between B cells, lymphoid stromal cells, and Tfh is thus considered as the core niche of FL pathogenesis.

Using human samples and original mouse models, our project aims at modeling and tracking the B-cell/stromal cell crosstalk considering kinetic and spatial heterogeneity with the objective to identify original therapeutic approaches. We thus address:

• Transcriptomic and spatial landscape of tumor microenvironment in human and mouse models of FL progression
• Functional consequences and targeting of the crosstalk between malignant B cells and their corrupted microenvironment