Journal
MOLECULAR ONCOLOGY
Volume 14, Issue 3, Pages 571-589Publisher
WILEY
DOI: 10.1002/1878-0261.12616
Keywords
CD206; lymphoma; macrophages; tumor microenvironment
Categories
Funding
- Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, BMBF) [BMBF-FKZ 0316166E, 0316166G, 031A428A, 031A428B, 031A428D]
- Deutsche Krebshilfe [70112502]
- Wilhelm Sander-Stiftung [2018.037.1]
- Interreg V [BY-CZ118]
- 'Stiftung der Georg-August-Universitat' (Kubeschka/Stricker/Wirth-Stiftung)
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Macrophages (M phi) are abundantly present in the tumor microenvironment and may predict outcome in solid tumors and defined lymphoma subtypes. M phi 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 M phi (TAM). Here, we show that the global mRNA expression and protein abundance of human M phi differentiated in Hodgkin lymphoma (HL)-conditioned medium (CM) differ from those of M phi 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 M phi; 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 M phi 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.
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