Background: Circular RNAs (circRNAs), a novel class of noncoding RNAs, have recently drawn much attention in the pathogenesis of human cancers. However, the role of circRNAs in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we aimed to identify novel circRNAs that regulate ESCC progression and explored their regulatory mechanisms and clinical significance in ESCC.Methods: Differentially expressed circRNAs between ESCC and paired adjacent normal tissues were identified using microarrays. The effects of a specific differentially expressed circRNA (circGSK3β) on tumor progression were explored in vitro and in vivo. Plasma samples from patients with ESCC, benign lesions and healthy controls were subjected to droplet digital PCR (ddPCR) analyses for circGSK3β, and the detection rates of plasma circGSK3β for ESCC were investigated.Results: We demonstrated that upregulated expression of circGSK3β was positively associated with advanced clinical stage and poor outcome in patients with ESCC. We further revealed that circGSK3β promoted ESCC cell migration and invasion via direct interaction with GSK3β and inhibiting GSK3β activity, providing a novel mechanism of circRNA in cancer progression. Importantly, we identified that circGSK3β expression in plasma was a biomarker for detection of ESCC and early stage of ESCC with the area under curve (AUC) of 0.782 and 0.793, respectively.Conclusions: CircGSK3β exerts critical roles in promoting ESCC metastasis and may serve as a novel therapeutic target for ESCC patients. The plasma level of circGSK3β have potential to serve as a novel diagnostic and prognostic biomarker for ESCC detection.

Key Points Platelet-derived microparticles inhibit IL-17 and IFN-γ production by Tregs and stimulate Treg stability in an inflammatory environment. Platelet-derived microparticles inhibit Treg plasticity in a P-selectin– and partially CXCR3-dependent manner.

Regulatory T cells (Treg) are well-known for their immune regulatory potential and are essential for maintaining immune homeostasis. The rationale of Treg-based immunotherapy for treating autoimmunity and transplant rejection is to tip the immune balance of effector T cell-mediated immune activation and Treg-mediated immune inhibition in favor of Treg cells, either through endogenous Treg expansion strategies or adoptive transfer of ex vivo expanded Treg. Compelling evidence indicates that Treg show properties of phenotypic heterogeneity and instability, which has caused considerable debate in the field regarding their correct use. Consequently, for further optimization of Treg-based immunotherapy, it is vital to further our understanding of Treg proliferative, migratory, and suppressive behavior. It is increasingly appreciated that the functional profile of immune cells is highly dependent on their metabolic state. Although the metabolic profiles of effector T cells are progressively understood, little is known on Treg in this respect. The objective of this review is to outline the current knowledge of human Treg metabolic profiles associated with the regulation of Treg functionality. As such information on human Treg is still limited, where information was lacking, we included insightful findings from mouse studies. To assess the available evidence on metabolic pathways involved in Treg functionality, PubMed, and Embase were searched for articles in English indexed before April 28th, 2019 using “regulatory T lymphocyte,” “cell metabolism,” “cell proliferation,” “migration,” “suppressor function,” and related search terms. Removal of duplicates and search of the references was performed manually. We discerned that while glycolysis fuels the biosynthetic and bioenergetic needs necessary for proliferation and migration of human Treg, suppressive capacity is mainly maintained by oxidative metabolism. Based on the knowledge of metabolic differences between Treg and non-Treg cells, we additionally discuss and propose ways of how human Treg metabolism could be exploited for the betterment of tolerance-inducing therapies.

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive pro-inflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis reveals no specific inflammatory endotypes in COVID-19 patients. Functional assays reveal abrogated adaptive cytokine production (interferon-gamma, interleukin-17 and interleukin-22) and prominent T cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlight potential biomarkers of disease severity.