A Complicated Neighborhood: Insights into the Hodgkin Lymphoma Microenvironment

Classical Hodgkin Lymphoma (cHL) is a heterogenous and complex biological entity. Whereas early studies focussed on characterization of the Reed-Sternberg (RS) cell, there is now increasing recognition of the importance of the tumor microenvironment (TME). This critical but only partially understood component of cHL biology is likely to impact pathogenesis, chemo-sensitivity and long-term outcome. Here, the non-malignant infiltrate is variably comprised of macrophages, regulatory T cells, and stroma, with the relative composition varying by histological sub-type. Notably, relative to other B cell lymphomas, cHL expresses high levels of immune checkpoint receptors such as PD-1 and LAG3, and immune checkpoint ligands such as PD-L1, PD-L2, the latter of which are frequently the subject of genetic amplifications. Hence the bi-directional relationship between the microenvironment and the malignant cell is now a valid target. Breakthroughs in our understanding of the TME in cHL have contributed to its status as the 'poster-child' for how checkpoint blockade can de-activate tumor-tolerance to induce meaningful clinical benefit. A further layer of complexity within the TME is the potential aetiological relationship between cHL and the Epstein-Barr virus, a ubiquitous virus found to reside within the RS cells in 40% of cases, particularly in those cases that have mixed cellularity. Unlike benign EBV-infected B cells, within RS cells the virus is in a highly aberrant latency state with expression of the viral oncoprotein LMP1, a virus that is known to induce immunosuppression and drive PD-L1 expression through the NFkB and the JAK-STAT pathways. But numerous unanswered mechanistic questions remain, not least in the light of the frequent genetically driven deficiencies in antigen presentation present in RS cells, particularly in cases of nodular sclerosing disease. This has reignited debate about the relative roles of adaptive and innate immunity in this disease. Remaining questions that need to be addressed include the evolution of the interaction between the TME and the malignant compartment during the course of cHL, the role of other immune checkpoints and their impact on combinatorial immune based strategies, and the contribution to immune-evasion played by stromal cells. Further understanding will assist the rational development of new immune-based strategies, and potentially one day a chemo-free regimen that is as clinically efficacious but less toxic than current chemotherapies.