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A number of drug treatments are known to alter the dialogue between the gut microbiota and the immune system components in the digestive mucosa. Alterations in intestinal homeostasis are now well known to affect peripheral immune responses and favor the occurrence of a number of pathologies such as allergies and cancers. Erythropoietin's known pleiotropic effects might explain the adverse events sometimes observed in anemic patients treated by erythropoiesis-stimulating agents (ESA). However, the impact of this therapeutic cytokine on the homeostasis of the intestinal tract has not previously been investigated in detail. By studying a mouse model of erythropoietin (EPO) supplementation for 28 days, we observed EPO-induced dysbiosis of the fecal microbiota characterized by a greater bacterial load, lower bacterial diversity and taxonomic changes. With regard to the mucosal immune system, an analysis of leukocyte populations in the small intestine and colon treatment revealed low proportions of ileal CD4 lymphocyte subpopulations (Treg, Tr17 and Th17 cells), IgA-secreting plasma cells, and a major macrophage subpopulation, involved in the control of lymphocyte responses. Our results provide for the first time a descriptive analysis of intestinal EPO's regulatory properties and raise questions about the involvement of EPO-induced alterations in the microbiota and the gut immune effectors in the control of intestinal and peripheral immune responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Sarrabayrouse, Joulain, Bessoles, Chiron, Abina and Hacein-Bey-Abina.)

The adverse effects observed in some cancer patients treated with erythropoiesis-stimulating agents such as erythropoietin (EPO) might be due to the latter's well-known immunosuppressive functions. Here, we used a mouse model of syngeneic triple-negative breast cancer to explore EPO's immunomodulatory role in a tumour setting. Our results showed that EPO treatment promotes tumour growth, exacerbates the 'immune desert', and results in a 'cold tumour'. EPO treatment changed the immune cell distribution in peripheral blood, secondary lymphoid organs, and the tumour microenvironment (TME). Our in-depth analysis showed that EPO mainly impacts CD4 T cells by accelerating their activation in the spleen and thus their subsequent exhaustion in the TME. This process is accompanied by a general elevation of CD39 expression by several immune cells (notably CD4 T cells in the tumour and spleen), which promotes an immunosuppressive TME. Lastly, we identified a highly immunosuppressive CD39 + regulatory T cell population (ICOS + , CTLA4 + , Ki67 + ) as a potential biomarker of the risk of EPO-induced tumour progression. EPO displays pleiotropic immunosuppressive functions and enhances mammary tumour progression in mice., (© 2024 The Author(s). Immunology published by John Wiley & Sons Ltd.)

Thrombopoietin (TPO), through activation of its cognate receptor Mpl, is the major regulator of platelet production. However, residual platelets observed in TPO- and Mpl-loss-of-function (LOF) mice suggest the existence of an additional factor to TPO in platelet production. As erythropoietin (EPO) exhibited both in vitro megakaryocytic potential, in association with other early-acting cytokines, and in vivo platelet activation activity, we sought to investigate its role in this setting. Here, we used multiple LOF models to decipher the reciprocal role of EPO and TPO in the regulation of platelet production in TPO-LOF and Mpl-LOF mice and of platelet size heterogeneity in wild-type mice. We first identified EPO as the major thrombopoietic factor in the absence of the TPO-Mpl pathway. Based on the study of several mouse models we found that the EPO-EPO receptor pathway acts on late-stage megakaryopoiesis and is responsible for large-sized platelet production, while the TPO-Mpl pathway promotes small-sized platelet production. On the basis of our data, EPO might be used for thrombocytopenia supportive therapy in congenital amegakaryocytopoiesis. Furthermore, as a distribution skewed toward large platelets is an independent risk factor and a poor prognosis indicator in atherothrombosis, the characterization of EPO's role in the production of large-sized platelets, if confirmed in humans, may open new perspectives in the understanding of the role of EPO-induced platelets in atherothrombosis., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Most diseases have multifactorial origins and their study requires complex in vivo validation strategies selected for their particular relevance. Most of the in vivo models used to date have been selected according to their availability and the accessibility of the corresponding technology platform. With the rapid development of new technologies, an increasing number of relevant systems for in vivo target validation are now available. In this review, we present in vivo loss-of-function tools acting at three biological levels (the gene, the messenger RNA and the protein); we discuss the specificity of each strategy and how the three techniques can be combined during the validation process in order to overcome the limitations of each one. Thus, combination will broaden the spectrum of the available validation systems and will enable target validation that predicts the situation in humans as accurately as possible.

Breast cancer is one of the most threatening women health diseases worldwide and its molecular heterogeneity offers a range of response to therapy. The role of polyamine metabolism is receiving increasing attention. Polyamine metabolism not only plays an important role in the occurrence and development of breast cancer, but also interacts with tumor immune microenvironment. In this work, we applied single-cell RNA-sequencing (scRNA-seq) and systems immunological approaches to interrogate immune cell infiltration gene-to-gene co-expressions in the bulk tumor transcriptomes of breast cancer. We acquired breast cancer sample data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), evaluated the infiltration status of 22 immune cell types using CIBERSORTx tool, respectively. By leveraging the Retrospective Breast sample of various technologies including gene expression and methylation, we identified 46 breast cancer proliferation-associated co-expression modules using weighted gene coexpression network analysis (WGCNA) approach along with machine learning models which in turn delineated single cell level expressions features that these selected module possessed. We observed substantial cellular heterogeneity in the breast cancer microenvironment, where lineage-specific gene expression patterns were highly associated with tumor progression. Moreover, we also identified the gene modules correlated with immune cell infiltration level that could function as regulators in response to tumors for immune therapy. Moreover, risk scores were correlated with immune cell function in different patient groups defined by high- and low-risk. The findings of this study shed a new light upon molecular classification prognostic assessment and personalized treatment in breast cancer. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs), which are antigen presenting cells of potential use in human antitumor vaccination trials, are presently the subject of intense investigation. Many recent studies have reported the possibility of generating ex vivo large numbers of DCs with high antigen presenting capacity by the culture of bone marrow or blood progenitors. In this study, we examined the differentiation into DCs of CD34+ progenitors isolated from the G-CSF mobilized blood of 3 healthy donors and 5 patients with breast cancer and cultured in the presence of GM-CSF + IL-13. The characteristics of the cells were compared to those of cells obtained in the presence of GM-CSF + TNF alpha. By day 15, one third of the bulk cells cultured with IL-13 were CD1a+/CD14- and strongly expressed CD1c, CD40, CD80 and HLA-DR. In contrast, cells obtained with TNF alpha expressed CD1a on one in three cells but with a considerably lower fluorescence intensity than on IL-13-cultured cells and strongly expressed CD14 on more than 50% of cells. CD1a+/CD14- cells emerged in IL-13 cultures at day 5, while in TNF alpha cultures CD14+ cells appeared before CD1a+ cells. Cells grown in the presence of IL-13 had an increased capacity to present antigens to autologous lymphocytes and to stimulate allogeneic T-lymphocytes. This effect was greater than that of cells grown in the presence of TNF alpha. These cells should therefore have greater effector potential in any therapeutic applications in humans.

Background: Periodontal disease (PerioD) is a chronic, complex inflammatory condition resulting from the interaction between subgingival dysbiotic bacteria and the host immune response leading to local inflammation. Since periodontal inflammation is characterized by multiple cytokines effects we investigated whether Periodontal Inflamed Surface Area (PISA), a continuous measure of clinical periodontal inflammation is a predictor of composite indexes of salivary cytokines. Methods and findings: In a cross-sectional study of 67 healthy, well-educated individuals, we evaluated PISA and several cytokines expressed in whole stimulated saliva. Two salivary cytokine indexes were constructed using weighted and unweighted approaches based on a Principal Component Analysis [named Cytokine Component Index (CCI)] or averaging the (standardized) level of all cytokines [named Composite Inflammatory Index (CII)]. In regression analysis we found that PISA scores were significantly associated with both salivary cytokine constructs, (CCI: part R = 0.51, p<0.001; CII: part R = 0.40, p = 0.001) independent of age, gender and BMI showing that single scores summarizing salivary cytokines correlated with severity of clinical periodontal inflammation. Conclusions: Clinical periodontal inflammation may be reflected by a single score encompassing several salivary cytokines. These results are consistent with the complexity of interactions characterizing periodontal disease. In addition, Type I error is likely to be avoided. [ABSTRACT FROM AUTHOR]

The discovery of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, together with an improved insight in dendritic cell biology illustrating their key function in the immune system, have provided a rationale to initiate dendritic cell-based cancer immunotherapy trials. Nevertheless, dendritic cell vaccination is in an early stage, as methods for preparing tumor antigen presenting dendritic cells and improving their immunostimulatory function are continuously being optimized. In addition, recent improvements in immunomonitoring have emphasized the need for careful design of this part of the trials. Still, valuable proofs-of-principle have been obtained, which favor the use of dendritic cells in subsequent, more standardized clinical trials. Here, we review the recent developments in clinical DC generation, antigen loading methods and immunomonitoring approaches for DC-based trials. [ABSTRACT FROM AUTHOR]