Acute Lymphoblastic Leukaemia Cells Impair Dendritic Cell and Macrophage Differentiation: Role of BMP4

Abstract

Dendritic cells and macrophages are common components of the tumour immune microenvironment and can contribute to immune suppression in both solid and haematological cancers. The Bone Morphogenetic Protein (BMP) pathway has been reported to be involved in cancer, and more recently in leukaemia development and progression. In the present study, we analyse whether acute lymphoblastic leukaemia (ALL) cells can affect the differentiation of dendritic cells and macrophages and the involvement of BMP pathway in the process. We show that ALL cells produce BMP4 and that conditioned media from ALL cells promote the generation of dendritic cells with immunosuppressive features and skew M1-like macrophage polarization towards a less pro-inflammatory phenotype. Likewise, BMP4 overexpression in ALL cells potentiates their ability to induce immunosuppressive dendritic cells and favours the generation of M2-like macrophages with pro-tumoral features. These results suggest that BMP4 is in part responsible for the alterations in dendritic cell and macrophage differentiation produced by ALL cells.

Three-dimensional bioprinting of multicell-laden scaffolds containing bone morphogenic protein-4 for promoting M2 macrophage polarization and accelerating bone defect repair in diabetes mellitus

“…BMP-4 directly induces the osteogenic differentiation of BMSCs by activating the Smad signaling pathway [ 38 ]. Recently, many studies have reported that BMPs induce the polarization of M2 type macrophages [ 41 , 42 , 57 , 58 ]. Lee et al [ 57 ] reported that BMP-6 secreted by renal cancer cells can bind to BMPR-II on macrophages and then phosphorylate Smad5 in target cells.…”

“…Recently, many studies have reported that the expression of BMP-4 is decreased in the serum of patients with DM and the calvarial defects of a DM rat model [ 39 , 40 ]. In addition, Martínez et al and Valencia et al reported that BMP-4 could induce macrophages to the M2 type by enhancing the secretion of IL-10 [ 41 , 42 ]. Therefore, BMP-4 may be a viable loading cytokine for 3D bioprinting to stimulate the healing of bone defects in patients with DM.…”

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

“…M2 macrophages stimulate mesenchymal stem cell proliferation and osteogenic differentiation through BMP-2 signaling (53). Conversely, in acute lymphoblastic leukemia BMP-4 is secreted to drive anti-inflammatory myeloid phenotypes, with dendritic cell immunosuppressive polarization, reduced M1 pro-inflammatory signature, and increased M2 macrophage generation (10). BMP-4 secreted from bladder cancer cell lines favored the polarization of monocytes and macrophages into the M2 macrophage phenotype (54).…”

“…BMPs regulate myeloid potential indirectly through stromal osteoblast lineages for increased homing of HSCs in bone marrow (8,9). Acute lymphoblastic leukemia cells produce BMP-4 to impair differentiation of macrophages and dendritic cells, and maintain a unique pro-tumorigenic microenvironment (10). BMP-2 ligand promotes immunomodulation of macrophages and their induction of bone marrow stroma ontogenesis (11).…”

Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies

“…Though both capable of expressing M2-associated genes, splenic TAMs stimulated the proliferation of T-ALL cells more potently compared to BM-TAMs, demonstrating the highly plastic nature of TAMs under different microenvironments [24]. Valencia et al also reported that ALL cells released Bone Morphogenetic Protein 4 (BMP4) to induce immunosuppressive dendritic cells and generate M2-like macrophages, which produced low TNFα and high CCL2, IL-6 and IL-10 [25]. Lastly, a recent report found that stromal interaction molecule 1 (STIM1) and STIM2 mediated the pathologic cancer-induced inflammation in the TME of T-cell ALL.…”