Protumoral role of monocytes in human B-cell precursor acute lymphoblastic leukemia: involvement of the chemokine CXCL10

Abstract Myelomonocytic cells play a key role in the progression of many solid tumors. However, very little is known about their contribution to the progression of hematopoietic cancers. We investigated the role of monocytes in the progression of human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We demonstrated that coculturing human monocytes in vitro with CD19+ BCP-ALL blasts from patients "conditioned" them to an inflammatory phenotype characterized by significant up-regulation of the chemokine, CXCL10. This phenotype was also observable ex vivo in monocytes isolated from BCP-ALL patients, which show elevated CXCL10 production compared with monocytes from healthy donors. Functionally, the "conditioned" monocytes promoted migration and invasive capacity of BCP-ALL cells. Increased invasion was mediated by matrix metalloproteinase 9 expression and activity in the BCP-ALL cells induced by the monocyte-derived CXCL10. However, neither the "conditioned" monocytes nor the CXCL10 produced by these cells had any effect on the proliferation/viability of BCP-ALL cells and angiogenesis. Collectively, our results strongly suggest a protumoral role for human monocytes in BCP-ALL, orchestrated by CXCL10 and its effect on tumor cell migration and invasion. These observations highlight the importance of the CXCL10/CXCR3 chemokine circuit in BCP-ALL progression

Radioprotective Activity of Naturally Occurring Organosulfur Compounds

The radioprotective effects of naturally occurring sulfur compounds and isothiocyanates such as diallyl sulfide (DAS), diallyl disulfide (DADS), allyl methyl sulfide (AMS), allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) have been investigated in whole body irradiated Swiss albino mice. Administration of these sulfur compounds could reduce the serum content of alkaline phosphatase (ALP), which was elevated after irradiation (23.9 ± 1.82 KA units). The elevated liver content of glutamate pyruvate transaminase (GPT) in control animals (76.2 ± 2.2 U/mL) after irradiation was significantly reduced in DAS (58.93 ± 4 U/mL) and AMS (55.7 ± 2.2 U/mL) treated animals. Elevated levels of lipid peroxides in serum and liver of irradiated control animals were also significantly reduced by treatment with these sulfur compounds. The glutathione (GSH) content in liver and intestinal mucosa was drastically reduced after irradiation. All the sulfur compounds and isothiocyanates could effectively enhance the GSH content of intestinal mucosa and liver. Findings at histopathological analysis of the intestine proved to be correlated with the above results. </jats:p

NR4A1 (Nur77) dependent monocytes patrol the lung vasculature and inhibit tumor cell invasion (P5068)

Abstract The nuclear receptor NR4A1 (Nur77) is expressed in monocytes and macrophages, yet its function in regulating inflammation associated with cancer is uncertain. Our previous studies identified that Nur77 regulates the development of patrolling Ly6C- monocytes and is involved in the resolution of inflammation. In the current study, we sought to determine how absence of Nur77 in hematopoietic cells impacts tumor growth and metastasis. Mice deficient in Nur77 showed a significant increase in growth and lung metastasis of syngeneic B16F10 melanoma. Increased tumor seeding of the lung was visible after only 4 days post IV tumor transfer, and appears to be specific to the lung. In vivo imaging reveals that Nur77-defficient mice have a drastic reduction in cells patrolling the lung vasculature, and that these patrolling monocytes establish early immune interactions with tumor cells and granulocytes in the lung. Furthermore, over-expression of Nur77 in human monocytes inhibited angiogenesis and invasion of human tumor cells in co-culture assays. We conclude that the absence of Nur77-regulated patrolling monocytes in combination with polarization of myeloid cells towards a pro-inflammatory and pro-angiogenic phenotype contributes to early tumor cell invasion of the vasculature and growth in the lung. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages in inflammatory diseases, including cancers.</jats:p

TLR4 signals through islet macrophages to alter cytokine secretion during diabetes

Toll-like receptors (TLRs), particularly TLR4, may act as immune sensors for metabolic stress signals such as lipids and link tissue metabolic changes to innate immunity. TLR signalling is not only tissue-dependent but also cell-type dependent and recent studies suggest that TLRs are not restricted to innate immune cells alone. Pancreatic islets, a hub of metabolic hormones and cytokines, respond to TLR signalling. However, the source of TLR signalling within the islet remain poorly understood. Uncovering the specific cell source and its role in mediating TLR signalling, especially within type 2 diabetes (T2D) islet will yield new targets to tackle islet inflammation, hormone secretion dysregulation and ultimately diabetes. In the present study, we immuno-characterised TLRs linked to pancreatic islets in both healthy and obese diabetic mice. We found that while TLRs1–4 and TLR9 were expressed in mouse islets, these TLRs did not co-localise with insulin-producing β-cells. β-Cells from obese diabetic mice were also devoid of these TLRs. While TLR immunoreactivity in obese mice islets increased, this was driven mostly by increased islet endothelial cell and islet macrophage presence. Analysis of human islet single-cell RNA-seq databases revealed that macrophages were an important source of islet TLRs. However, only TLR4 and TLR8 showed variation and cell-type specificity in their expression patterns. Cell depletion experiments in isolated mouse islets showed that TLR4 signalled through macrophages to alter islet cytokine secretome. Together, these studies suggest that islet macrophages are a dominant source of TLR4-mediated signalling in both healthy and diabetic islets.</jats:p

NF-κB pathway orchestrates the tumor promoting role of monocytes/macrophages in human renal cell carcinoma (66.45)

Abstract Growing evidences suggests that monocyte/macrophages play crucial role in cancer progression. Even though studies in transgenic mouse tumor models have demonstrated the role of myelomonocytic cells in various aspects of tumor progression, information on the role of these cells in human cancers is limited. We investigated the role of monocytes/macrophages in the progression of a human renal Cell Carcinoma (RCC). Gene expression studies have shown that RCC associated monocytes (RCC-Mo) under basal condition exhibit a proinflammatory and protumoral phenotype characterized by high expression of genes such as TNFA, IL6, VEGFA, IL8 and MMP9. Surprisingly, when these cells were exposed to inflammatory stimuli, such as Lipid A or TNF-α, they failed to show an up- regulation of proinflammatory cytokines such as TNFA, CCL3, IL6, and IL1B. This observation correlated to the tumor-induced immunosuppression observed in the patients. Signaling studies showed that the inflammatory/protumoral phenotype of TAMs under basal condition was regulated through NF-κB pathway.Further studies demonstrated defective NF-κB signaling was responsible for the “refractory state” of this RCC-Mo to further inflammatory stimuli. In vivo studies in a human RCC mouse model validated our above findings. In conclusion these results are the first to characterize the transcriptomal and functional phenotype of tumor associated monocytes/macrophages in human cancer which suggested their tumor promoting role.</jats:p