Elucidating the role of IRF4 in reprogramming the tumor microenvironment in follicular lymphoma

We hypothesize that increased IRF4 expression disrupts the immune synapse between B cells and T follicular helper (TFH) cells while promoting suppressive T follicular regulatory (TFR) cells, in part by preventing induction of selection molecules such as CD40 and PDL1, and in part by rewiring cytokines release. To test our hypothesis, we propose three specific aims. In Aim 1, we will use novel transgenic mouse models with overexpression and deletion of irf4 to investigate whether and how IRF4 controls tumor immunity in normal and malignant B cells by integrating single-cell transcriptional and translational (CITE-seq) analysis.

In Aim 2, we will use high dimensional cytometry (CyTOF), spatially resolved proteomics (CODEX), and CITE-seq in the same mouse models to define the effect of B cells with different IRF4 status on TFH cells. In Aim 3, we will use single-cell transcriptomic and proteomic tools to elucidate the role of TFR cells in response to B cells differently expressing IRF4. The findings of all aims will be validated in human FL samples.