Fabbi M.,Laboratory of Biotherapy |
Carbotti G.,Laboratory of Biotherapy |
Ferrini S.,Laboratory of Biotherapy
Journal of Leukocyte Biology | Year: 2015
IL-18 is a proinflammatory and immune regulatory cytokine, member of the IL-1 family. IL-18 was initially identified as an IFN-γ-inducing factor in T and NK cells, involved in Th1 responses. IL-18 is produced as an inactive precursor (pro-IL-18) that is enzymatically processed into amature form by Casp 1. Different cells, such as macrophages, DCs, microglial cells, synovial fibroblasts, and epithelial cells, express pro-IL-18, and the production of bioactive IL-18 is mainly regulated at the processing level. PAMP or DAMP molecules activate inflammasomes, which trigger Casp1 activation and IL-18 conversion. The natural inhibitor IL-18BP, whose production is enhanced by IFN-γ and IL-27, further regulates IL-18 activity in the extracellular environment. Inflammasomes and IL-18 represent double-edged swords in cancer, as their activation may promote tumor development and progression or oppositely, enhance anti-tumor immunity and limit tumor growth. IL-18 has shown antitumor activity in different preclinical models of cancer immunotherapy through the activation of NK and/or T cell responses and has been tested in clinical studies in cancer patients. However, the dual role of IL-18 in different experimental tumor models and human cancers raises critical issues on its therapeutic use in cancer. This review will summarize the biology of the IL-18/IL- 18R/IL-18BP system and will address the role of IL-18 and its inhibitor, IL-18BP, in cancer biology and immunotherapy. © Society for Leukocyte Biology.
Stigliani S.,Physiopathology of Human Reproduction |
Croce M.,Laboratory of Biotherapy |
Morandi F.,Laboratory of Oncology |
Scaruffi P.,Physiopathology of Human Reproduction |
And 8 more authors.
BioMed Research International | Year: 2015
The prognosis of children with metastatic neuroblastoma (NB) > 18 months at diagnosis is dismal. Since the immune status of the tumor microenvironment could play a role in the history of disease, we evaluated the expression of CD45, CD14, ARG1, CD163, CD4, FOXP3, Perforin-1 (PRF1), Granzyme B (GRMB), and IL-10 mRNAs in primary tumors at diagnosis from children with metastatic NB and tested whether the transcript levels are significantly associated to event-free and overall survival (EFS and OS, resp.). Children with high expression of CD14, ARG1 and FOXP3 mRNA in their primary tumors had significantly better EFS. Elevated expression of CD14, and FOXP3 mRNA was significantly associated to better OS. CD14 mRNA expression levels significantly correlated to all markers, with the exception of CD4. Strong positive correlations were found between PRF1 and CD163, as well as between PFR1 and FOXP3. It is worth noting that the combination of high levels of CD14, FOXP3, and ARG1 mRNAs identified a small group of patients with excellent EFS and OS, whereas low levels of CD14 were sufficient to identify patients with dismal survival. Thus, the immune status of the primary tumors of high-risk NB patients may influence the natural history of this pediatric cancer. © 2015 Sara Stigliani et al.
De Cecco L.,Functional Genomics and Bioinformatics |
Capaia M.,Laboratory of Biotherapy |
Zupo S.,Laboratory of Molecular Diagnostics |
Cutrona G.,Laboratory of Molecular Diagnostics |
And 9 more authors.
PLoS ONE | Year: 2015
Several factors support CLL cell survival in the microenvironment. Under different experimental conditions, IL21 can either induce apoptosis or promote CLL cell survival. To investigate mechanisms involved in the effects of IL21, we studied the ability of IL21 to modulate gene and miRNA expressions in CD40-activated CLL cells. IL21 was a major regulator of chemokine production in CLL cells and it modulated the expression of genes involved in cell movement, metabolism, survival and apoptosis. In particular, IL21 down-regulated the expression of the chemokine genes CCL4, CCL3, CCL3L1, CCL17, and CCL2, while it up-regulated the Th1-related CXCL9 and CXCL10. In addition, IL21 down-regulated the expression of genes encoding signaling molecules, such as CD40, DDR1 and PIK3CD. IL21 modulated a similar set of genes in CLL and normal B-cells (e.g. chemokine genes), whereas other genes, including MYC, TNF, E2F1, EGR2 and GAS-6, were regulated only in CLL cells. An integrated analysis of the miRNome and gene expression indicated that several miRNAs were under IL21 control and these could, in turn, influence the expression of potential target genes. We focused on hsa-miR-663b predicted to down-regulate several relevant genes. Transfection of hsa-miR-663b or its specific antagonist showed that this miRNA regulated CCL17, DDR1, PIK3CD and CD40 gene expression. Our data indicated that IL21 modulates the expression of genes mediating the crosstalk between CLL cells and their microenvironment and miRNAs may take part in this process. © 2015 De Cecco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.