Expression of IL‐34 correlates with macrophage infiltration and prognosis of diffuse large B‐cell lymphoma

Abstract

Objectives Infiltration of macrophages through the tyrosine kinase receptor CSF1R is a poor prognosis factor in various solid tumors. Indeed, these tumors produce CSF1R ligand, macrophage colony‐stimulating factor (M‐CSF) or interleukin‐34 (IL‐34). However, the significance of these cytokines, particularly, the newly discovered IL‐34 in haematological malignancies, is not fully understood. We therefore analysed the role of IL‐34 in diffuse large B‐cell lymphoma (DLBCL), the most common subtype of malignant lymphoma. Methods We analysed formalin‐fixed paraffin‐embedded lymphoma tissues of 135 DLBCL patients for the expression of IL‐34 and the number of macrophages, and the survival of these patients. The expression of IL‐34 in DLBCL cell lines and the activity of IL‐34 to induce the migration of monocytic cells were also characterised. Results Several lymphoma tissues showed a clear IL‐34 signal, and such signal was detectable in 36% of patients. DLBCL cell lines also expressed IL‐34. Interestingly, the percentage of IL‐34+ patients in the activated B‐cell subtype was significantly higher than that in the germinal centre B‐cell subtype. More interestingly, IL‐34+ patients showed shorter survival periods and higher number of macrophages in lymphoma tissues. The recruitment of monocytes is likely the first step for the higher macrophage density in the IL‐34+ lymphoma tissues. Indeed, IL‐34 induced the migration of monocytic cells. Conclusion Our results raise the possibility that IL‐34 in lymphoma tissues of DLBCL patients recruits monocytes, leading to the higher number of macrophages in the tissues and poor prognosis of patients. IL‐34 may be an additional therapeutic target of DLBCL.

Integrative Statistics, Machine Learning and Artificial Intelligence Neural Network Analysis Correlated CSF1R with the Prognosis of Diffuse Large B-Cell Lymphoma

“…Therefore, the hypothesis was that CSF1R in DLBCL identified only TAMs. In DLBCL, high CD163-positive TAMs have been associated with poor prognosis of the patients [9,10,12], which is the same result seen by gene expression in the LLMPP series. Nevertheless, the presence of a B-cell pattern was not expected.…”

“…The tumor-associated macrophages (TAMs) are of special interest because the ones with an M2-like phenotype have tumor-promoting capabilities [9], which involve tumor proliferation, invasion, angiogenesis, metastasis, and suppression of anti-tumor immunity [10,11]. In DLBCL, it has been reported that high numbers are associated with a poor prognosis of DLBCL [9,12].…”

Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages

“…Macrophages were analyzed for the expression of KLF2, KLF4, c-Myc, c-Maf, MafB, or PU.1 mRNA followed by the normalization to the mRNA level of GAPDH, as described previously 37 . In brief, RNA was isolated using the ISOGEN II reagent (Nippon Gene, Tokyo, Japan), and each cDNA was prepared using M-MLV RT (Invitrogen).…”

Drainage of inflammatory macromolecules from the brain to periphery targets the liver for macrophage infiltration

“…The receptor tyrosine kinase CSF1R (also known as Fms) pathway regulates migration, differentiation, proliferation, and survival at varying degrees of different tissue-resident macrophages and monocytes in mammals and zebrafish ( Oosterhof et al, 2018 ; Kuil et al, 2019 ). Recent studies have implicated a role for this pathway in macrophage recruitment in disease, including the assembly of tumor-associated macrophages in various cancers ( Noyori et al, 2019 ; Lin et al, 2019 ; Zins et al, 2018 ; Baghdadi et al, 2016 ; Baghdadi et al, 2018 ). Of particular interest IL-34 is elevated and implicated in the inflammation process of several inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, and Sjogren’s syndrome ( Ciccia et al, 2013 ; Hwang et al, 2012 ; Moon et al, 2013 ; Chemel et al, 2012 ; Boulakirba et al, 2018 ).…”