Macrophages and dendritic cells as actors in the immune reaction of classical Hodgkin lymphoma.

Christiane Silke Tudor,Armin Gerbitz,Maike Julia Buettner,Heiko Bruns,Christoph Daniel,Arndt Hartmann,Luitpold Valentin Distel,Riccardo Dolcetti

doi:10.1371/journal.pone.0114345

Christiane Silke Tudor, Armin Gerbitz + Show 6 more

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https://doi.org/10.1371/journal.pone.0114345

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Abstract

BackgroundThe inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Here, we focussed on the role of macrophages (MΦ) and dendritic cells (DC).MethodsMΦ and DC infiltration was investigated in 106 cHL specimens using immunohistochemistry and cytokine expression was analyzed in a subset by real-time PCR. Human peripheral blood-derived monocytes, DC, MΦ stimulated with GM-CSF (MΦGM-CSF, pro-inflammatory MΦ-1-model) or M-CSF (MΦM-CSF, immunomodulatory MΦ-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). DC maturation or MΦ polarization were investigated by flow cytometry. Furthermore, the impact of DC or MΦ on cHL cell proliferation was analyzed by BrdU/CFSE assay.ResultsIn cHL tissues mature myeloid (m)DC and MΦ predominated. High numbers of CD83+ mDC and low numbers of CD163+ MΦ were associated with improved disease specific survival. In numerous cHL specimens increased levels of both pro- and anti-inflammatory cytokines and of IL13 and GM-CSF were observed compared to reactive lymphadenopathies. Maturation of DC and induction and maintenance of an immunomodulatory MΦ phenotype were promoted by SN derived from cHL cell lines. TNFα neutralization in SN resulted in a significant inhibition of mDC maturation. DC and pro-inflammatory MΦ inhibited the proliferation of cHL cells.ConclusionAdopting an immunomodulatory phenotype is a potential mechanism for how MΦ promote immune evasion in cHL. Mature DC, in contrast, might participate in antitumoral immunity.

Highlights

Intense attention has been paid to antigen-presenting cells (APC) as part of the tumor stroma
CD1a and CD83 were used as markers of immature and mature Myeloid dendritic cells (mDC) as described elsewhere [1] (Figure 1 A and B)
In classical Hodgkin lymphoma (cHL) the majority of mDC could be identified as mature CD83+ mDC and a significantly minor portion as CD1a+ immature mDCs (Figure 1 F)

Summary

Introduction

Intense attention has been paid to antigen-presenting cells (APC) as part of the tumor stroma. Among tumor-infiltrating APC tumor-associated macrophages (TAM) predominate [4, 5]. In classical Hodgkin lymphoma (cHL) few malignant Hodgkin-Reed-Sternberg (HRS) cells are embedded in a prominent inflammatory infiltrate [6, 7]. An inhibitory effect on DC maturation by tumoral production of mediators like IL10, TGFb and M-CSF has been proposed [1]. The inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Human peripheral blood-derived monocytes, DC, MW stimulated with GM-CSF (MWGM-CSF, pro-inflammatory MW-1-model) or M-CSF (MWM-CSF, immunomodulatory MW-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). Results: In cHL tissues mature myeloid (m)DC and MW predominated. Maturation of DC and induction and maintenance of an immunomodulatory MW phenotype were promoted by SN derived from cHL cell lines. DC and pro-inflammatory MW inhibited the proliferation of cHL cells

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