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

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.

PD-1 and LAG-3 Checkpoint Blockade: Potential Avenues for Therapy in B-Cell Lymphoma

“…PD-L2 expression is also induced on inflammatory macrophages by IL-4 [ 25 ]. A recent study by Arlt et al, confirms the capacity of HRS cells to attract monocytes and drive their differentiation to TAMs [ 69 ].…”

Dupilumab and cutaneous T-cell lymphoma

“…Conditioned media from Hodgkin lymphoma cells support tumor-associated macrophage differentiation and lymphoma dissemination through upregulation of surface antigens regulated by IL-13. 3 Breast-implantassociated anaplastic large-cell lymphoma is typically effusion limited, with good prognosis after implant removal. Although cytokine expression profiling typically reveals a type 17 helper T cell (Th)/Th1 signature, a Th2 allergic inflammatory response is suggested by the presence of IL-13, and Janus kinaseesignal transducer and activator of transcription proteins (JAK-STAT) gain-of-function mutations may be present.…”

Potential role of M2 TAMs around lymphatic vessels during lymphatic invasion in papillary thyroid carcinoma

“…The results of this study are similar, and it is possible that cancer cells infiltrate the basement membrane of lymphatic vessels by coexisting with macrophages. In addition, in Hodgkin lymphoma, the more CD206-positive TAMs are present, the more tumour tissue remodelling advances and then promotes dissemination 18 . Although the M1/M2 polarity of macrophages cannot be simplified, there are many other reports showing that M2 TAMs act as tumour promoters, and we also believe that M2 TAMs have a tumour-promoting effect in PTC.…”