NR4A1-P53 AXIS IN THE IMMUNE EVASION OF AGGRESSIVE LYMPHOMAS

Aggressive lymphomas are among the most common types of lymphoid cancers and consist of Burkitts lymphoma, diffuse large B cell lymphoma (DLBCL), follicular lymphoma grade 3. While checkpoint blockade therapies (CBTs) have emerged as a promising avenue to counteract tumor evasion, this treatment form comes with substantial cost burdens and often rely on trial-and-error approaches. Importantly, only a small percentage of lymphoma patients (10-20%) respond favorably to CBT, partly due to the limited understanding of the regulation of immune checkpoints during lymphoma development and the absence of predictive biomarkers. Our recent investigations have shed light on key factors contributing to poor outcomes in patients with DLBCL. We observed significant decreases in the levels of NR4A1 and p53, which are important regulators of gene expression and known tumor suppressors, alongside high expression of checkpoint components. In mice, depletion of NR4A1 led to reduced p53 levels, accelerated lymphoma development, and increased expression of immune- inhibitory checkpoint components, particularly in animals with intact immune systems. These and other findings suggest a functional relationship involving NR4A1, p53, and the orchestrating immune evasive mechanisms in aggressive lymphomas. Our proposed research project aims to address this axis by developing new mouse models with specific and inducible deletion of NR4A1 and/or p53 in B cells. Using advanced molecular and genomic techniques, we will comprehensively study lymphoma development in these models. We will also implement a tissue fluid sampling method to repeatedly measure cytokine signals and cellular changes within evolving tumors, providing valuable insights into the lymphoma microenvironment. By leveraging these models, we aim to tailor CBTs based on the status of NR4A1 and p53. To clinically validate our findings, we will analyze a large cohort of lymphoma samples from GRAZ lymphoma cohort and compare them with publicly available datasets. Ultimately, our goal is to functionally establish the clinical relevance of the NR4A1-p53-checkpoint axis and identify new biomarkers that can help guide treatment decisions involving checkpoint inhibitors for aggressive lymphomas. Through our research, we are poised to improve outcomes for patients with aggressive lymphomas by developing more effective and personalized treatment strategies.