Immune Landscape in Burkitt Lymphoma reveals M2-macrophage polarization and Correlation between PD-L1 expression and Non-Canonical EBV latency program

Abstract

BACKGROUND: The Tumor Microenviroment (TME) is a complex milieu that is increasingly recognized as a key factor in multiple stages of disease progression and responses to therapy as well as escape from immune surveillance. However, the precise contribution of specific immune effector and immune suppressor components of the TME in Burkitt lymphoma (BL) remains poorly understood.METHODS: In this paper, we applied the computational algorithm CIBERSORT to Gene Expression Profiling (GEP) datasets of 40 BL samples to draw a map of immune and stromal components of TME. Furthermore, by multiple immunohistochemistry (IHC) and multispectral immunofluorescence (IF), we investigated the TME of additional series of 40 BL cases to evaluate the role of the Programmed Death-1 and Programmed Death Ligand-1 (PD-1/PD-L1) immune checkpoint axis. RESULTS: Our results indicate that M2 polarized macrophages are the most prominent TME component in BL. In addition, we investigated the correlation between PD-L1 and latent membrane protein-2A (LMP2A) expression on tumour cells, highlighting a subgroup of BL cases characterized by a non-canonical latency program of EBV with an activated PD-L1 pathway. CONCLUSION: In conclusion, our study analysed the TME in BL and identified a tolerogenic immune signature highlighting new potential therapeutic targets.

Comparative analysis of post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation reveals differences in the tumor microenvironment

“…The composition and clinicopathological features of our PTLD collective are comparable to published data, although we had a relatively high percentage of polymorphic PTLD with a total of 23/48 cases (48% vs 19% [32]/28% [33]) [4]. Important parameters determining the classification of PTLD are EBV status and the specific immunodeficiency setting [3,5,6,24]. Although the percentage of EBV-negative PTLD after SOT has increased in recent years, the relatively high number of EBV-negative cases after HCT (5/26) is surprising [34] including two unusual EBV-negative cases, a polymorphic PTLD occurring 3 months after HCT and an EBVnegative non-destructive PTLD in the form of plasmacytic hyperplasia occurring 23 months after HCT [6].…”

“…The composition of the tumor microenvironment plays a pivotal role in the pathogenesis of tumors and has been shown to be of prognostic importance [14,24,39,40]. Due to the unique immunologic setup in PTLD patients, the characterization of the TME is of great interest and may have therapeutic implications.…”

“…In PTLD, the number of TAMs and their polarization appear to correlate with EBV status [23]. Macrophage polarization has been shown to be associated with the T cell composition of tumors [16] as well as prognosis in lymphoma [17,18,24,25].…”

A Spatially Resolved Dark- versus Light-Zone Microenvironment Signature Subdivides Germinal Center-Related Aggressive B Cell Lymphomas

“…In particular, 56 of 70 BLs (80%) were clustered in the DZ-like cluster according to the 53-genes DZ/LZ signature. This finding was of particular interest if we consider that BL represents a rather homogeneous disease as far as the biological features of the malignant clone are concerned, and that the recently reported variability in BL immune landscape ( Granai et al., 2020 ) may configure different microenvironment scenarios more similar to or distinct from the immunologically cold DZ.…”

Targeted Therapies for Epstein-Barr Virus-Associated Lymphomas

“…Moreover, it has been suggested that the tumor microenvironment in EBV-associated lymphomas is rich in PD-1/PD-L1 active engagements, and PD-1 expressing tumor-infiltrating lymphocytes are associated more with EBV-positive tumors [ 78 , 80 ]. A subset of BL samples are characterized by M2-macrophage polarization, activated PD-L1 expression, and non-canonical LMP2A expression in the tumor microenvironment [ 81 ]. EBV-positive DLBCL cells exhausted T-cells and induced their PD-1 expression in vitro; however, introducing a PD-1 blockade can restore T-cell activity [ 82 ].…”