The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape

Abstract

It has become clear that cancer is not merely a growth of autonomously proliferating cells, but that other non-malignant cell types are a functional part of the disease. Immune cells, fibroblasts, specialized mesenchymal cells and microvasculature together make up the tumour microenvironment and have functional interactions with tumour cells. Classical Hodgkin's lymphoma (cHL) is characterized by only a few malignant cells and an abundance of inflammatory cells. Hodgkin and Reed-Sternberg (HRS) cells are surrounded by T and B cells admixed with plasma cells, macrophages, eosinophils and mast cells. A constitutive activity of NF-kappaB and an altered JAK-STAT signalling pathway are part of the biological background associated with the increased expression of cytokines and cytokine receptors seen in HRS cells. Over-expression of the members of the TNF receptor family, especially CD30 and CD40, is a hallmark of HRS cells. cHL is a tumour where aberrant cytokine production contributes not only to the proliferation of HRS cells but also to the maintenance of an appropriate environment for the tumour cells. In addition, several chemokines contribute to the composition of the inflammatory background in cHL. This review summarizes updated information on the complex interactions between the HRS cells and their tissue microenvironment and highlights the development of newer therapeutic strategies aimed at targeting the non-malignant inflammatory/immune cellular components of HL that are involved in cancer cell growth and/or immune escape.

The H3K27me3 demethylase, KDM6B, is induced by Epstein–Barr virus and over-expressed in Hodgkin's Lymphoma

“…However, its over-expression in tumours, which test negative for EBV points to additional regulatory mechanisms. NFkB is constitutively activated in both EBV positive and in EBV negative tumours, and has been shown to regulate the expression of KDM6B in macrophages (De Santa et al, 2007;Aldinucci et al, 2010). However, we found no evidence to suggest that NFkB regulates KDM6B expression in HL cells (Supplementary Figure 1), consistent with reports that NFkB is not involved in oncogene or stress-induced upregulation of KDM6B in human diploid fibroblasts (Agger et al, 2009).…”

Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin’s lymphoma

“…5 These characteristic Reed-Sternberg cells reside in a milieu of an extensive but ineffective T-cell infiltrate. 6 EBV is often associated with Hodgkin's lymphoma and causes overexpression of PD-L1 on tumor cells. 7 PD-1 inhibitors nivolumab and pembrolizumab have both been studied in relapsed Hodgkin's lymphoma with promising initial results.…”

The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells

“…These inflammatory cells are attracted by cytokines and chemokines secreted by the malignant cell population. 1,2 The complex interactions between HRS cells and bystander cells create a specific microenvironment that is thought to be critical for growth and survival of HRS cells. A detailed analysis of signals evoked by these interactions does not only contribute to a better understanding of HL pathogenesis, but might also provide a basis for the development of new treatment strategies.…”