Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13

We undertook a comprehensive analysis of circulating myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) in pancreatic, esophageal and gastric cancer patients and investigated whether MDSCs are an independent prognostic factor for survival. We evaluated a series of plasma cytokines and in particular re-evaluated the Th2 cytokine interleukin-13 (IL-13). Peripheral blood was collected from 131 cancer patients (46 pancreatic, 60 esophageal and 25 gastric) and 54 healthy controls. PBMC were harvested with subsequent flow cytometric analysis of MDSC (HLADR− Lin1low/− CD33+ CD11b+) and Treg (CD4+ CD25+ CD127low/− FoxP3+) percentages. Plasma IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, IL-17, G-CSF, IFN-γ, TNF-α and VEGF levels were analyzed by the Bio-Plex cytokine assay. Plasma arginase I levels were analyzed by ELISA. MDSCs and Tregs were statistically significantly elevated in pancreatic, esophageal and gastric cancer compared with controls, and MDSC numbers correlated with Treg levels. Increasing MDSC percentage was associated with increased risk of death, and in a multivariate analysis, MDSC level was an independent prognostic factor for survival. A unit increase in MDSC percentage was associated with a 22% increased risk of death (hazard ratio 1.22, 95% confidence interval 1.06–1.41). Arginase I levels were also statistically significantly elevated in upper gastrointestinal cancer patients compared with controls. There was Th2 skewing for cytokine production in all three diseases, and importantly there were significant elevations of the pivotal Th2 cytokine interleukin-13, an increase that correlated with MDSC levels

Neuroinflammatory signals enhance the immunomodulatory and neuroprotective properties of multipotent adult progenitor cells

Introduction: Stem cell-based therapies are currently widely explored as a tool to treat neuroimmune diseases. MAPC (Multipotent Adult Progenitor Cells) have been suggested to have strong immunomodulatory and neuroprotective properties in several experimental models. In this study, we investigate whether MAPC are of therapeutic interest for neuroinflammatory disorders such as multiple sclerosis (MS), by evaluating their capacities to modulate crucial pathological features and gain insights in the molecular pathways involved. Methods: Rat MAPC (rMAPC) were treated with combinations of pro-inflammatory cytokines that are closely associated with neuroinflammatory conditions, a process called licensing. mRNA expression of immunomodulatory molecules, chemokines and chemokine receptors was investigated. The migratory potential of licensed rMAPC towards a broad spectrum of chemokines was tested in a Transwell assay. Furthermore, the effect of licensing on the ability of rMAPC to attract and suppress the proliferation of encephalitogenic T cells was assessed. Finally, neuroprotective properties of rMAPC were determined in the context of protection from oxidative stress of oligodendrocytes. Therefore, rMAPC were incubated with conditioned medium of OLN93 cells subjected to sub-lethal doses of hydrogen peroxide (H2O2) and the gene expression of neurotrophic factors was assessed. Results: After licensing, a wide variety of immunomodulatory molecules and chemokines, including Nitric Oxide synthase (iNOS) and fractalkine, was up-regulated by rMAPC. The migratory properties of rMAPC towards various chemokines were also altered. In addition, rMAPC were found to inhibit antigen specific T cell proliferation and this suppressive effect was further enhanced after pro-inflammatory treatment. This phenomenon was partially mediated through iNOS or cyclooxygenase-2 (COX-2). Activated rMAPC secreted factors that led to attraction of myelin specific T cells. Finally, exposure of rMAPC to in vitro simulated neurodegenerative environment induced the up-regulation of mRNA levels of vascular endothelial growth factor (VEGF) and ciliary neurotrophic factor (CNTF). Factors secreted by rMAPC in response to this environment partially protected OLN93 cells from H2O2 induced cell death. Conclusions: rMAPC possess immune modulatory and neuroprotective properties which are enhanced in response to neuroinflammatory signals. These findings thereby warrant further research to evaluate MAPC transplantation as a therapeutic approach in diseases with an immunological and neurodegenerative component such as MS.The authors would like to thank Ms. Katrien Wauterickx, Ms. Christel Bocken and Mr. Jo Janssen (Hasselt University, Biomedical Research institute) for overall technical assistance. Additionally, we gratefully thank Ms. Ellen Van Houtven (ReGenesys) for her assistance in designing the migration assays. This research was supported by the Belgian Charcot Foundation

Generation of myeloid-derived suppressor cells using prostaglandin E2

Myeloid-derived suppressor cells (MDSCs) are natural immunosuppressive cells and endogenous inhibitors of the immune system. We describe a simple and clinically-compatible method of generating large numbers of MDSCs, using the cultures of peripheral blood-isolated monocytes supplemented with prostaglandin E2 (PGE2). We observed that PGE2 induces endogenous COX2 expression in cultured monocytes, blocking their differentiation into CD1a+ DCs and inducing the expression of IDO1, IL-4Ralpha, NOS2 and IL-10, typical MDSC-associated suppressive factors. The establishment of a positive feedback loop between PGE2 and COX2, the key regulator of PGE2 synthesis is necessary and sufficient to promote the development of CD1a+ DCs to CD14+CD33+CD34+ monocytic MDSCs in GM-CSF/IL-4-supplemented monocyte cultures, for their stability, production of multiple immunosuppressive mediators and CTL-suppressive function. In addition to PGE2, also selective EP2- and EP4-agonists, but not EP3/1 agonists, induce the MDSCs development, suggesting that other activators of the EP2- and EP2-driven signaling pathway (adenylate cyclase/cAMP/PKA/CREB) may be used to promote the development of suppressive cells. Our observations provide for a simple method to generate large numbers of MDSCs for the immunotherapy of autoimmune diseases, chronic inflammatory disorders and transplant rejection

A meta-analysis of correlated behaviours with implications for behavioural syndromes: Mean effect size, publication bias, phylogenetic effects and the role of mediator variables

In evolutionary and behavioural ecology, increasing attention is being paid to the fact that functionally distinct behaviours are often not independent from each other. Such phenomenon is labelled as behavioural syndrome and is usually demonstrated by phenotypic correlations between behaviours like activity, exploration, aggression and risk-taking across individuals in a population. However, published studies disagree on the strength, and even on the existence of such relationships. To make general inferences from this mixed evidence, we quantitatively reviewed the literature using modern meta-analytic approaches. Based on a large dataset, we investigated the overall relationship between behaviours that are expected to form a syndrome and tested which factors can mediate heterogeneities in study outcomes. The average strength of the phenotypic correlation between behaviours was weak; we found no effect of the phylogeny of species but did observe significant publication bias. However, even accounting for this bias, the mean effect size was positive and statistically different from zero (r = 0. 198). Effect sizes showed considerable heterogeneity within species, implying a role for population-specific adaptation to environmental factors and/or between-study differences in research design. There was a significant positive association between absolute effect size and repeatability of behaviours, suggesting that within-individual variation of behavioural traits can set up an upper limit for the strength of the detected phenotypic correlations. Moreover, spatial overlap between the contexts in which different behaviours were assayed increased the magnitude of the association. The small effect size for the focal relationship implies that a huge sample size would be required to demonstrate a correlation between behaviours with sufficient statistical power, which is fulfilled only in very few studies. This suggests that behavioural syndromes often remain undetected and unpublished. Collectively, our meta-analysis revealed a number of points that might be worth to consider in the future study of behavioural syndromes. © 2012 The Author(s).Peer Reviewe