Molecular characterisation of nodular sclerosing classical Hodgkin lymphoma derived fibroblasts and their beneficial interaction with Hodgkin Reed Sternberg cells

  • Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas in Western Europe. The nodular sclerosing subtype of cHL (NS cHL) is characterised by a proliferation of fibroblasts in the tumour microenvironment, leading to fibrotic bands surrounding the lymphoma infiltrate. Several studies have described a crosstalk between the tumour cells of cHL, the Hodgkin- and Reed-Sternberg (HRS) cells, and cancerassociated fibroblasts (CAF). However, to date a deep molecular understanding of these fibroblasts is lacking. Aim of the present study therefore was a comprehensive characterisation of these fibroblasts. Moreover, only a few studies describe the interplay of HRS cells and CAF. The paracrine communication and direct interaction of these two cellular fractions have been investigated within this study. Finally, the influence of a few HRS cells within a lymph node orchestrate the mere alteration of its architecture and morphology. Gene expression and methylation profiles of fibroblasts isolated from primary lymph node suspensions revealed persistent differences between fibroblasts obtained from NS cHL and lymphadenitis. NS cHL derived fibroblasts exhibit a myofibroblastic - inflammatory phenotype characterised by MYOCD, CNN1 and IL-6 expression. TIMP3, an inhibitor of matrix metalloproteinases, was strongly upregulated in NS cHL fibroblasts, likely contributing to the accumulation of collagen in sclerotic bands of NS cHL. Treatment by luteolin could reverse this fibroblast phenotype and decrease TIMP3 secretion. NS cHL fibroblasts showed enhanced proliferation when they were exposed to soluble factors released from HRS cells. For HRS cells, soluble factors from fibroblasts were not sufficient to protect them from Brentuximab-Vedotin(BV) induced cell death. However, HRS cells adherent to fibroblasts were protected from BV-induced injury. The cHL specific interaction of both cell fractions reveals an initiation of inflammatory key regulators such as IL13 and IL4. Among important adhesion molecules known from literature the blocking of integrin beta 1 solely interrupted the adhesion of HRS cells to CAF. In summary, this study proves the stable reprograming of CAF phenotype and expression derived from NS cHL. It presents a suitable in vitro model for studying the interaction of HRS cells and CAF by paracrine factors and adherence. Most importantly the observations confirm the importance of fibroblasts for HRS cells´ inflammatory niche and cell survival associated with TIMP3 which probably acts as a major factor to the typical accumulation of fibrosis observed in NS cHL.

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Author:Katrin BankovORCiDGND
Place of publication:Frankfurt am Main
Referee:Rolf MarschalekORCiDGND, Sylvia HartmannORCiDGND
Advisor:Sylvia Hartmann
Document Type:Doctoral Thesis
Date of Publication (online):2021/01/27
Year of first Publication:2020
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Granting Institution:Johann Wolfgang Goethe-Universität
Date of final exam:2021/01/12
Release Date:2021/02/11
Tag:cancer associated fibroblasts; classical Hodgkin lymphoma; tumor microenvironment
Page Number:134
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoDeutsches Urheberrecht