Molecular biology of Hodgkin lymphoma

Abstract

Classical Hodgkin lymphoma (cHL) is unique among lymphoid malignancies in several key biological features. (i) The Hodgkin and Reed-Sternberg (HRS) tumor cells are rare among an extensive and complex microenvironment. (ii) They derive from B cells, but have largely lost the B-cell typical gene expression program. (iii) Their specific origin appears to be pre-apoptotic germinal center (GC) B cells. (iv) They consistently develop bi- or multinucleated Reed-Sternberg cells from mononuclear Hodgkin cells. (v) They show constitutive activation of numerous signaling pathways. Recent studies have begun to uncover the basis of these specific features of cHL: HRS cells actively orchestrate their complex microenvironment and attract many distinct subsets of immune cells into the affected tissues, to support their survival and proliferation, and to create an immunosuppressive environment. Reed-Sternberg cells are generated by incomplete cytokinesis and refusion of Hodgkin cells. Epstein-Barr virus (EBV) plays a major role in the rescue of crippled GC B cells from apoptosis and hence is a main player in early steps of lymphomagenesis of EBV⁺ cHL cases. The analysis of the landscape of genetic lesions in HRS cells so far did not reveal any highly recurrent HRS cell-specific lesions, but major roles of genetic lesions in members of the NF-κB and JAK/STAT pathways and of factors of immune evasion. It is perhaps the combination of the genetic lesions and the peculiar cellular origin of HRS cells that are disease defining. A combination of such genetic lesions and multiple cellular interactions with cells in the microenvironment causes the constitutive activation of many signaling pathways, often interacting in complex fashions. In nodular lymphocyte predominant Hodgkin lymphoma, the GC B cell-derived tumor cells have largely retained their typical GC B-cell expression program and follicular microenvironment. For IgD-positive cases, bacterial antigen triggering has recently been implicated in early stages of its pathogenesis.

Fig. 1. Hallmarks of HRS cells and cHL.

Shown are hallmark features of HRS cells and the microenvironment in cHL.

Fig. 2. Microenvironmental interactions in cHL supporting HRS-cell survival and proliferation.

Shown are main cellular interactions in the cHL microenvironment that promote the survival and/or proliferation of HRS cells. The HRS cell-supporting immune cells and fibroblasts are actively recruited into the microenvironment by a multitude of cytokines and chemokines secreted by the HRS cells. HRS cells in many cHL cases still express MHC class II, so that in addition to the interactions between HRS cells and CD4⁺ Th cells shown also a binding of MHC class II to the TCR is possible (not depicted).

Fig. 3. Immune evasion mechanisms in cHL.

Shown are main mechanisms how HRS cells escape from an attack by cytotoxic T cells and NK cells. Several factors promote the production and reduce the degradation of extracellular adenosin (ADO), which inhibits the function of CD8⁺ T cells (see main text). Indoleamine 2,3-dioxygenase (IDO) is intracellularly expressed by macrophages and dendritic cells (not shown) in the HL microenvironment and reduces the extracellular levels of tryptophan, which impairs the function of cytotoxic T cells and NK cells. The immunosuppressive function of CD137 is thought to be mediated in an indirect fashion: CD137 on HRS cells and CD137 transmitted to other immune cells through trogocytosis promote the internalization of CD137L, thereby reducing the level of this costimulatory factor for T cell activity. The downregulation of NKG2D-L on HRS cells is mediated by exoenzymes that cleave it from the surface of HRS cells. Whereas MHC class I is downregulated by most cases of cHL, loss of MHC class II expression is seen only in a subset of cases.