High CD206 levels in Hodgkin lymphoma-educated macrophages are linked to matrix-remodeling and lymphoma dissemination.

Annekatrin Arlt,Sarah Reinke,Katharina Limm,Tobias Pukrop,Julia C Engelmann,Wolfram Gronwald,Christian Dullin,Wolfram Klapper,Jörg Wilting,Katja Dettmer,Franziska Linke,Frederike Von Bonin,Xueni Sun,Thorsten Rehberg,Peter J Oefner,Martina Vockerodt,Gertrude Bunt,Dieter Kube,Rainer Spang,Rieke Specht,Markus Maulhardt,Paula Pérez-Rubio

doi:10.1002/1878-0261.12616

Abstract

Macrophages (Mφ) are abundantly present in the tumor microenvironment and may predict outcome in solid tumors and defined lymphoma subtypes. Mφ heterogeneity, the mechanisms of their recruitment, and their differentiation into lymphoma‐promoting, alternatively activated M2‐like phenotypes are still not fully understood. Therefore, further functional studies are required to understand biological mechanisms associated with human tumor‐associated Mφ (TAM). Here, we show that the global mRNA expression and protein abundance of human Mφ differentiated in Hodgkin lymphoma (HL)‐conditioned medium (CM) differ from those of Mφ educated by conditioned media from diffuse large B‐cell lymphoma (DLBCL) cells or, classically, by macrophage colony‐stimulating factor (M‐CSF). Conditioned media from HL cells support TAM differentiation through upregulation of surface antigens such as CD40, CD163, CD206, and PD‐L1. In particular, RNA and cell surface protein expression of mannose receptor 1 (MRC1)/CD206 significantly exceed the levels induced by classical M‐CSF stimulation in M2‐like Mφ; this is regulated by interleukin 13 to a large extent. Functionally, high CD206 enhances mannose‐dependent endocytosis and uptake of type I collagen. Together with high matrix metalloprotease9 secretion, HL‐TAMs appear to be active modulators of the tumor matrix. Preclinical in ovo models show that co‐cultures of HL cells with monocytes or Mφ support dissemination of lymphoma cells via lymphatic vessels, while tumor size and vessel destruction are decreased in comparison with lymphoma‐only tumors. Immunohistology of human HL tissues reveals a fraction of cases feature large numbers of CD206‐positive cells, with high MRC1 expression being characteristic of HL‐stage IV. In summary, the lymphoma‐TAM interaction contributes to matrix‐remodeling and lymphoma cell dissemination.

Highlights

The tumor microenvironment (TME) plays an important role in numerous malignancies and may even provide a tumor supportive milieu
Hodgkin lymphoma cell supernatants attract monocytes and initiate their differentiation into Mφ characterized by high mannose receptor 1 expression
gene expression (GE) of Mφ was analyzed by RNA-Seq and compared between Mφ treated with L428-conditioned media (CM), diffuse large B-cell lymphoma (DLBCL)-CM, and macrophage colony-stimulating factor (M-CSF), respectively (Fig. 1; Table S1 and S2)

Summary

Introduction

The tumor microenvironment (TME) plays an important role in numerous malignancies and may even provide a tumor supportive milieu. Among the stromal cells found in the TME, tumor-attracted and re-educated macrophages (Mφ), designated as tumor-associated Mφ (TAM), have received increasing interest (Mantovani and Sica, 2010; Twum et al, 2017). They are involved in various aspects of tumor progression like aberrant cytokine secretion, immune check point modulation, tumor matrix remodeling, angiogenesis, and resistance to treatment (Mantovani et al, 2017, 2002; Mantovani and Sica, 2010). The present study sheds new light on the molecular interaction between HL cells and TAMs and shows that HL-educated TAMs are capable of supporting tissue remodeling and lymphoma dissemination involving the mannose receptor 1 (MRC1/CD206)

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Discussion

Conclusion