Modulation of regulatory T cell suppression in tumors through OX40

Tumor cells develop numerous mechanisms to escape from the control exerted by the immune system. One of these strategies is the accumulation of regulatory T cells (Treg) within the tumor, which keep effector T cells (Teff) and dendritic cells (DC) in an inactive state. An efficient approach to overcome the inhibitory potential of Treg focuses on OX40, a costimulatory molecule constitutively expressed by Treg and induced in activated Teff. The treatment of mouse transplantable tumor models with the mAb OX86, the agonist of OX40, induces tumor rejection by acting on both these T cell subsets. In this study we investigated the fine cellular mechanisms at the basis of this process, dissecting the effects of OX86 on Treg and on CD4+Foxp3-CD44highCD62LlowOX40+ effector memory T cells (Tem), which represent the most abundant Teff subset in the tumor. Upon OX40 stimulation, Treg are "contra-suppressed" and down-modulate the expression of the transcription factor interferon regulatory factor 1 (IRF1), thus reducing the secretion of IL- 10. Conversely OX86 provides activating stimuli to Tern, which up-regulate CD40L and in turn promote the maturation of DC. OX86 shifts the tumoral milieu from tolerogenic to immunogenic, favoring the activation and migration of DC from the tumor to the draining lymph node (dLN) and the subsequent new CTL induction. The relevance of OX40 in Treg biology goes beyond the modulation of their suppressive abilities. OX40 increases the sensitivity of Treg to IL-2, facilitating the phosphorylation of STAT5 through high level of the mirl55 and low level of SOCS1. The overexpression of miR155 endowed Treg of higher suppressive functions, further enhancing tumor growth. These data clearly remark the key roles exerted by OX40 in influencing Treg and Teff behavior. Understanding how to manipulate OX40 signaling will provide great advantage in the development of efficient therapy for both tumors and autoimmune diseases

Deus-Trindade: Paradigma Paras as Relacoes

The God of the creed and of the Christian liturgy the Holy Trinity - Father Son and Holy Spirit - was forgotten for almost 1 600 years This forgetfulness with the consequent christomonism experienced by Christians and also by the theological reflection was the reflection of a patriarchal monocratic society especially the feudal model in which the lord was the only one to have authority over the entire family group and of the servants and aggregates This model had important influences on human relations An example of this is the monarchical authoritarianism that prevailed in the West of the world Since the 19th century and the development of philosophy psychology and sociology theology also takes up together with the legacy of the Fathers of the Church the reflection on the Trinity based on these disciplines After the Second Vatican Council the compulsory resumption of the Trinitarian foundation of the theological disciplines is verified Today it is understood that the model of God-Trinity relationships is also valid for human relationships in which it is possible to experience in an always fallible and fleeting way God-Trinity in established relationship

FUNDAMENTOS DA ECLESIOLOGIA DE FRANCISCO

Este artigo versa sobre a eclesiologia do Papa Francisco, abordando alguns aspectos fundamentais: o redimensionamento da visão da Igreja de centralizada a localizada hierarquicamente; a recuperação da importância da centralidade da pessoa, ensinamento bimilenar da Doutrina Social da Igreja; o estímulo à “saída” das sacristias e templos em direção ao mundo e ao ser humano, na alegria missionária; e, concluindo, a constatação do paradigma trinitário no discurso e no modo de agir do Papa Francisco. Elementos fortes disso são: a “saída”, como provocação para uma Igreja missionária e voltada pra o outro; a pobreza, sinal inequívoco do seguimento de Cristo na atenção aos mais necessitados e como forma de valorização do essencial, em respeito ao outro e à natureza; a alegria, sinal do advento do Reino entre aqueles que vivem a fraternidade.Enviado: 30-12-2017 - Aprovado e publicado: 11-201

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

Mast cells infiltrating inflamed or transformed gut alternatively sustain mucosal healing or tumor growth

Mast cells (MC) are immune cells located next to the intestinal epithelium with regulatory function in maintaining the homeostasis of the mucosal barrier. We have investigated MC activities in colon inflammation and cancer in mice either wildtype (WT) or MC-deficient (KitW-sh) reconstituted or not with bone marrow-derived MCs. Colitis was chemically induced with dextran sodium sulfate (DSS). Tumors were induced by administering azoxymethane (AOM) intraperitoneally before DSS. Following DSS withdrawal, KitW-sh mice showed reduced weight gain and impaired tissue repair compared with their WT littermates or KitW-sh mice reconstituted with bone marrowderived MCs. MCs were localized in areas of mucosal healing rather than damaged areas where they degraded IL33, an alarmin released by epithelial cells during tissue damage. KitW-sh mice reconstituted with MC deficient for mouse mast cell protease 4 did not restore normal mucosal healing or reduce efficiently inflammation after DSS withdrawal. In contrast with MCs recruited during inflammation-associated wound healing, MCs adjacent to transformed epithelial cells acquired a protumorigenic profile. In AOM- and DSS-treated WT mice, high MC density correlated with high-grade carcinomas. In similarly treated KitW-sh mice, tumors were less extended and displayed lower histologic grade. Our results indicate that the interaction of MCs with epithelial cells is dependent on the inflammatory stage, and on the activation of the tissue repair program. Selective targeting of MCs for prevention or treatment of inflammation-associated colon cancer should be timely pondered to allow tissue repair at premalignant stages or to reduce aggressiveness at the tumor stage

Osteopontin shapes immunosuppression in the metastatic niche.

The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impact is uncertain when produced by leukocytes in the context of the tumor stroma. In a broad study using Spp1(-/-) mice along with gene silencing in tumor cells, we obtained evidence of distinct and common activities of OPN when produced by tumor or host cells in a spontaneously metastatic model of breast cancer. Different cellular localization of OPN is associated with its distinct activities, being mainly secreted in tumor cells while intracellular in myeloid cells. OPN produced by tumor cells supported their survival in the blood stream, whereas both tumor- and host-derived OPN, particularly from myeloid cells, rendered the metastatic site more immunosuppressive. Myeloid-derived suppressor cells (MDSC) expanded with tumor progression at both primary and lung metastatic sites. Of the expanded monocytic and granulocytic cell populations of MDSCs, the monocytic subset was the predominant source of OPN. In Spp1(-/-) mice, the inhibition of lung metastases correlated with the expansion of granulocyte-oriented MDSCs. Notably, monocytic MDSCs in Spp1(-/-) mice were less suppressive than their wild-type counterparts due to lower expression of arginase-1, IL6, and phospho-Stat3. Moreover, fewer regulatory T cells accumulated at the metastatic site in Spp1(-/-) mice. Our data find correlation with lung metastases of human mammary carcinomas that are associated with myeloid cells expressing OPN. Overall, our results unveiled novel functions for OPN in shaping local immunosuppression in the lung metastatic niche

Reciprocal influence of B cells and tumor macro and microenvironments in the ApcMin/+model of colorectal cancer

One of the most fascinating aspects of the immune system is its dynamism, meant as the ability to change and readapt according to the organism needs. Following an insult, we assist to the spontaneous organization of different immune cells which cooperate, locally and at distance, to build up an appropriate response. Throughout tumor progression, adaptations within the systemic tumor environment, or macroenvironment, result in the promotion of tumor growth, tumor invasion and metastasis to distal organs, but also to dramatic changes in the activity and composition of the immune system. In this work, we show the changes of the B-cell arm of the immune system following tumor progression in the ApcMin/+model of colorectal cancer. Tumor macroenvironment leads to an increased proportion of total and IL-10-competent B cells in draining LNs while activates a differentiation route that leads to the expansion of IgA+lymphocytes in the spleen and peritoneum. Importantly, serum IgA levels were significantly higher in ApcMin/+than Wt mice. The peculiar involvement of IgA response in the adenomatous transformation had correlates in the gut-mucosal compartment where IgA-positive elements increased from normal mucosa to areas of low grade dysplasia while decreasing upon overt carcinomatous transformation. Altogether, our findings provide a snapshot of the tumor education of B lymphocytes in the ApcMin/+model of colorectal cancer. Understanding how tumor macroenvironment affects the differentiation, function and distribution of B lymphocytes is pivotal to the generation of specific therapies, targeted to switching B cells to an anti-, rather than pro-, tumoral phenotype

Persistent immune stimulation exacerbates genetically driven myeloproliferative disorders via stromal remodeling

Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated acute myelogenous leukemia (AML) patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy

Cardiac magnetic resonance in heart failure with preserved ejection fraction:myocyte, interstitium, microvascular, and metabolic abnormalities

Heart failure (HF) with preserved ejection fraction (HFpEF) is a chronic cardiac condition whose prevalence continues to rise, with high social and economic burden, but with no specific approved treatment. Patients diagnosed with HFpEF have a high prevalence of comorbidities and exhibit a high misdiagnosis rate. True HFpEF is likely to have multiple pathophysiological causes - with these causes being clinically ill-defined due to limitations of current measurement techniques. Myocyte, interstitium, microvascular, and metabolic abnormalities have been regarded as key components of the pathophysiology and potential therapeutic targets. Cardiac magnetic resonance (CMR) has the capability to look deeper with a number of tissue characterization techniques which are closer to the underlying specific abnormalities and which could be linked to personalized medicine for HFpEF. This review aims to discuss the potential role of CMR to better define HFpEF phenotypes and to infer measurable therapeutic targets

Fatty acid metabolism complements glycolysis in th selective regulatory t cell expansion during tumor growth

The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs’ advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs’ expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment