Feeding dendritic cells with tumor antigens: self-service buffet or à la carte?

Adoptive transfer of autologous dendritic cells (DC) presenting tumor-associated antigens initiate and sustain an immune response which eradicate murine malignancies. Based on these observations, several clinical trials are in progress testing safety and efficacy with encouraging preliminary reports. In these approaches, ex vivo incubation of DC with a source of tumor antigens is required to load the relevant antigenic epitopes on the adequate antigen presenting molecules. Recent data show that in some instances exogenous DC artificially injected into malignant tissue or endogenous DC attracted to the tumor nodule by means of gene transfer of GM-CSF and CD40L into malignant cells result in efficacious antitumor immunity. In the case of intratumoral injection of DC the procedure is curative only if DC had been genetically engineered to produce IL-12, IL-6 or to express CD40L. Evidence has been obtained showing that intratumoral DC can capture and process tumor antigens to be presented to T-lymphocytes. Although the exact mechanisms of tumor antigen acquisition by DC are still unclear, available data suggest a role for heat shock proteins released from dying malignant cells and for the internalization of tumor-derived apoptotic bodies. Roles for tumor necrosis versus apoptosis are discussed in light of the 'danger theory'

Angiopoietin decoy secreted at tumor site impairs tumor growth and metastases by inducing local inflammation and altering neoangiogenesis

The extracellular domain of the receptor tyrosine kinase Tie2/TEK (exTEK) has been used as an angiopoietin decoy to study the role of angiopoietins in the tumor-host interactions, using a syngeneic model of experimental metastases and subcutaneous tumor. Soluble exTEK secreted by transfected tumor cells inhibited HUVECs from forming tubes in Matrigel. ExTEK-transfected C26 colon carcinoma and TS/A mammary tumor cells displayed reduced growth rate when injected subcutaneously, and reduced ability to form experimental metastases when injected intravenously. Immunohistochemical analysis of tumors and metastases showed increased leukocytes infiltration and signs of inflammation in exTEK-secreting compared to parental tumor, as well as impairment in neo-vessel growth and organization. However, while neoangiogenesis eventually rescued in the subcutis, it failed to organize in the experimental metastases of exTEK-secreting tumor, contributing to the hampering of metastatic growth and to increased mice survival. The reactive infiltrate of C26TEK contained a different percentage of leukocytes and was responsible for the tumor inhibition. In fact, leukopenia induced by gamma-irradiation of recipient mice or injection into interferon gamma (IFN-gamma) gene knockout (GKO) mice resulted in reduced mouse survival and an increased number of lung metastases. On the other hand, interleukin (IL)-12 treatment prolonged the survival of mice bearing subcutaneous C26TEK but not of those bearing lung metastases, suggesting that IL-12 could exert further antiangiogenic effects at the site where the tumor can restore neoangiogenesis. These results show in vivo that reduced angiopoietin availability at the tumor site induces a local inflammatory response and impairment of neoangiogenesis which act synergistically to limit tumor growth and metastasis

A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2.

OX40 stimulation is known to enhance activation of effector T cells and to inhibit induction and suppressive function of Treg. Here we uncovered a novel role of OX40 in sustaining Treg competitive fitness in vivo, during repopulation of lymphopenic hosts and reconstitution of BM chimeras. Defective expansion of OX40-null Treg diminished their ability to suppress inflammation in a model of lymphopenia-driven colitis. OX40-mediated promotion of Treg fitness spanned beyond lymphopenic environments, as endogenous Treg in OX40-null mice showed decreased accumulation during thymic development, enhanced susceptibility to antibody-mediated depletion and defective turnover following thymectomy. In vitro, OX40-deficient Treg were found to be intrinsically hyporesponsive to IL-2, in terms of Stat5 phosphorylation and proliferation, according to elevated SOCS1 content and reduced miR155 expression. Therefore, OX40 is a key factor in shaping Treg sensitivity to IL-2 and promoting their proliferation and survival, toward accurate immune regulation

HOXB7: a key factor for tumo-associated angiogenic switch.

We had demonstrated previously a functional bridge between altered homebox (HOX) gene expression and tumor progression through HOXB7 transactivation of basic fibroblast growth factor. Here, we have studied whether HOXB7, in addition to basic fibroblast growth factor, may induce other genes directly or indirectly related to neoangiogenesis and tumor invasion. Parental, beta-galactosidase-transduced, and HOXB7-transduced SkBr3 cell lines were examined for the expression of several growth factors and growth factor receptors involved in the proliferative and angiogenic processes. Vascular endothelial growth factor, melanoma growth-stimulatory activity/growth-related oncogenene alpha, interleukin-8, and angiopoietin-2 were up-regulated by HOXB7 transduction. The exception was angiopoietin-1 expression that was abrogated. Additional analyses included the expression levels of enzymes such as matrix metalloprotease (MMP)-2 and MMP-9 and heparanase, capable of proteolytic degradation of extracellular matrix and basement membranes. Results showed an induction of only MMP-9. The functional implication of such a finding was tested using an in vitro coculture assay in a three-dimensional matrix. A delay of differentiation with persistent nests of proliferating cells was found in endothelial cells cocultured with HOXB7-transduced SkBr3 cells. Tumorigenicity of these cells has been evaluated in vivo. Xenograft into athymic nude mice showed that SkBr3/HOXB7 cells developed tumors in mice, either irradiated or not, whereas parental SkBr3 cells did not show any tumor take unless mice were sublethally irradiated. Comparison of tumor nodules for vascularization by CD-31 and CD-34 immunostaining revealed an increased number of blood vessels in tumors expressing HOXB7. Together, the results indicate HOXB7 as a key factor up-regulating a variety of proangiogenic stimuli. Thus, HOXB7 gene or protein is a target to aim at to inhibit tumor-associated neoangiogenesis, considering the number and the redundancy of proangiogenic molecules that should be targeted one by one to theoretically achieve the same effect

Condicionalidad reforzada a través de las cubiertas vegetales en olivar. Opinión de los agricultores

En el cultivo del olivar, en la última década, se ha implantado y extendido el uso de cubiertas vegetales como práctica cultural. El empleo de cubiertas vegetales en olivar se asocia a una multitud de efectos ambientales positivos y por tanto la implementación de estas en los olivares ha sido objeto de ayudas específicas en las medidas agroambientales de diferentes programas de desarrollo rural de Andalucía a partir del año 2000. Sin embargo, según los datos de la encuesta sobre Superficies y Rendimientos Cultivos del Ministerio de Agricultura, Pesca y Alimentación (Esyrce) las cubiertas vegetales en olivar sólo se emplean en alrededor de un 29% del total de la superficie del olivar andaluz. El objetivo de este trabajo es conocer la opinión de los agricultores con respecto a la puesta de cubiertas vegetales. Por ello se realizan 200 encuestas a olivareros y se determinan los factores de bloqueo y propiciadores a las mismas. Entre ellos, se analiza el impacto de una condicionalidad reforzada que obligue a los agricultores a usar cubiertas vegetales.El presente estudio ha sido financiado por el proyecto PR.AVA.AVA2019.031 cofinanciado al 80% por el Fondo Europeo de Desarrollo Regional, dentro del Programa Operativo FEDER de Andalucía 2014-2020

A Tour Within the Bis-Phenanthroline Copper Complex Family: from Electrochemical Features to Application as Redox Mediators in DSSCs

Sustainable energy production is one of the more serious challenges facing humanity to reduced and minimize the anthropogenic impact on the Planet. The conversion of the abundant solar light into energy is a promising solution. In this view photoelectrochemical devices such as dye-sensitized solar cells, DSSCs, and perovskite-based devices are among the most studied architectures for a direct production of electricity. The role of redox mediators in DSSCs was understated for at least a decade for the benefit of dye engineering resulting in a stagnation of cell conversion efficiency. The proposal of alternative redox couples to the classical I\u2013/I3\u2013 has opened the way towards new record performance (exceeding 14% at 1 sun, 1.5 AM). Electrochemistry could play a crucial role in the design of novel effective electron shuttles. Our work is aimed to reveal the potentiality of substituted bis-phenanthroline copper complexes as redox mediators in DSSCs, starting from a rationalization of their electrochemical features (i.e. E1/2 and kheter) as a function of ligand substituents. These structure vs activity relationships allowed to finely tune their electrochemical parameters to better fulfill features of ideal mediators. A tour around the electrochemical properties of these complexes will be presented together with results concerning formulation of efficient Cu-based electrolytes for DSSCs. Special attention will be paid to discuss correlations useful to draw a guideline for the synthesis of always best mediators. Acknowledgments SmartMatLab Centre for funding the research

Copper Complexes as Effective Competitors for Iodine-free Electrolytes in Dye-Sensitized Solar Cells

Dye-sensitized solar cells, DSSCs, are photoelectrochemical devices well contextualized within the global commitment for the progressive increase of the percentage of electric energy produced by renewable resources. In the last decade the development of novel redox mediators alternative to the ubiquitous iodine-based electrolyte (identified as one of the principal causes of the stagnant PCE values in which the research got bogged down) has been one of the hottest topic of research. Efforts of many scientists have been catalyzed by metal complexes as promising single electron mediators characterized by an easy modulation of many electrochemical and optical features requested to ideal electron shuttles. While tris(diimine) cobalt complexes largely monopolize recent literature, our group has focused on homoleptic 1,10-phenanthroline-based copper complexes relying on the fact that their intrinsic limitations, if suitable tailored, could represent the turning point toward a new generation of electron shuttles. Starting from \u201cstructure vs activity maps\u201d correlating ligand substitutions with the electrochemical features of this class of complexes, we have proposed convenient Cu-based redox couples based on bulky 2-substituted phenanthrolines that reached efficiency higher than 6%, more than doubling the PCE of cells filled with the unique benchmark copper-based redox shuttle (12/22, in figure below) and even exceeding performance of a control I\u2013/I3\u2013-based electrolyte

A Spatially Resolved Dark- versus Light-Zone Microenvironment Signature Subdivides Germinal Center-Related Aggressive B Cell Lymphomas

We applied digital spatial profiling for 87 immune and stromal genes to lymph node germinal center (GC) dark- and light-zone (DZ/LZ) regions of interest to obtain a differential signature of these two distinct microenvironments. The spatially resolved 53-genes signature, comprising key genes of the DZ mutational machinery and LZ immune and mesenchymal milieu, was applied to the transcriptomes of 543 GC-related diffuse large B cell lymphomas and double-hit (DH) lymphomas. According to the DZ/LZ signature, the GC-related lymphomas were subclassified into two clusters. The subgroups differed in the distribution of DH cases and survival, with most DH displaying a distinct DZ-like profile. The clustering analysis was also performed using a 25-genes signature composed of genes positively enriched in the non-B, stromal sub-compartments, for the first time achieving DZ/LZ discrimination based on stromal/immune features. The report offers new insight into the GC microenvironment, hinting at a DZ microenvironment of origin in DH lymphomas