Burkitt Lymphoma: from B-Cell Receptor activation to Tumor Microenvironment

Background: In Burkitt lymphoma (BL) macrophages represent the main component of TME giving rise to the characteristic histological aspect of the “starry sky” pattern. However, in some instances, BL may show a granulomatous reaction and such cases are associated with a favorable prognosis and occasionally spontaneous regression. Objectives.The aim of the present work was to thoroughly characterize the immune landscape of BL subtypes: 7 EBV-positive BL with granulomatous reaction, 8 EBV-positive BL with the typical starry sky pattern, 8 EBV- negative BL with the typical starry sky pattern. Design\Methods: Genes expression profiling (GEP) of 23 Formalin-Fixed Paraffin- Embedded (FFPE) samples were performed on the NanoString nCounter using the PanCancer Immune ProfilingPanel consisting of 730 immune-related genes and 40 housekeeping genes. Results: Based on unsupervised clustering of differentially expressed genes (DEGs) BL samples formed separated clusters, distinguishing EBV-positive BL with granulomatous reaction (cluster 1) from BL with typical starry sky, both EBV-positive and EBV-negative (cluster 2 and 3, respectively). We confirmed previous findings of differently enriched genes in NF-kB, JAK-STAT, BCR signaling pathways between EBV positive BL and EBV-negative BL. In addition, differences in immune response signature were identified between BL with granulomatous reaction and BL with typical starry sky. The TME signature in BL with starry sky pattern, both EBV- positive and EBV-negative, showed an up-regulation of M2 secreted chemokines (CCL22, CCL17, CCL2, CCR4), IL4/ IL13 pathway, M2-immune response genes (ARG1, ICOS, IDO1, LAG3, CD163, GATA3), immune checkpoint genes (CD274, PDCD1, PDCD1LG2, CTLA4) suggesting a M2- polarization in these cases. Conversely, these signatures were downregulated in BL with granulomatous reaction, resulting in a M1 polarization and a proinflammatory response. Conclusion: Due to their pivotal role, TAMs are promising targets for additional therapies in BL lymphoma and combining TAM-targeted therapy with conventional treatment may open up novel therapeutic avenues for therapy-refractory patients.