MicroRNA is small non-coding RNA and can lead to translational repression or target degradation by base-pairing with complementary sequences of mRNA molecules. MicroRNA-155 (miR-155), one of the most studied microRNA, is the first one to be reported as oncogenic [1]. miR-155 is over expressed in a long list of both hematological and solid tumors and is of paramount importance in cancer diagnosis and prognosis. However, how miR-155 particularly in host immune system regulates the tumor progression remains poorly understood. Our study underscores a contextual role of miR-155 in regulating tumor growth and tumor immunity via distinct immune subsets within tumors [2]. We conclude that the balance of different effects between those immune cell populations, which are regulated by miR-155, appears to determine whether miR-155 promotes or inhibits tumor growth [2].
We demonstrated that host miR-155 deficiency promoted antitumor T cell immunity in multiple transplanted tumor models. Further analysis of immune cell compartments revealed that miR-155 was required for the accumulation and suppressive function of myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Apart from the direct modulation on MDSC, miR-155 was also required for the MDSC-mediated CD4+Foxp3+ regulatory T cells (Treg) induction. On the other hand, miR-155 deficiency hampered the antitumor responses of both dendritic cells and T cells. Therefore, it appears that in our tumor models, miR-155 mediated a dominant immunosuppressive effect by MDSC, leading to the enhanced overall antitumor immunity in miR-155 deficient hosts.
Reduced colon inflammation and decreased colorectal carcinogenesis were also found in miR-155 deficient mice when azoxymethane (AOM) and dextran sodium sulphate (DSS) were combined to induce colon lesions. Furthermore, miR-155 was upregulated in MDSC either from tumor-bearing hosts or generated from bone marrow progenitors by GM-CSF and IL-6. These results support the notion that miR-155 is a prototypical microRNA bridging inflammation and cancer development [3]. Although miR-155 may regulate tumor growth in an intrinsic manner, it is likely that inflammation promotes the accumulation of functional MDSC by increased miR-155 that dampens the immune surveillance and antitumor immunity, thereby facilitating tumor growth.
To identify the molecular mechanisms by which miR-155 regulates MDSC (Figure (Figure1),1), we found that miR155 retained the suppressive activity of MDSCs through inhibiting SOCS1. Moreover, inverse correlations between miR-155 expression and SHIP-1/SOCS1 expression were established in MDSC. As SHIP-1 was recently reported as a target of miR155 specifically in MDSC expansion [4], these results suggest both SHIP-1 and SOCS1 as target genes of miR-155 during functional MDSC generation. SOCS1 also restricted arginase I activity [5], which otherwise would limit the efficiency of MDSC proinflammatory responses. Indeed, we showed that miR-155−/− MDSC has a lower level of arginase activity than WT counterparts, and inhibition of arginase-I with specific inhibitors completely abrogated the suppressive activity of WT MDSC and did not affect the miR-155−/− MDSC. Our data indicate that miR-155 may modulate arginase-dependent suppressive function of MDSC via targeting SOCS1.
Figure 1
miR-155 regulates tumor MDSC
More interestingly, we observed the decreased production of MMP-9 and VEGF from miR-155−/− MDSC, which would presumably limit the tumor angiogenesis. Given a contribution of miR-155 expression by cancer cells to tumor angiogenesis [6], further studies will determine whether miR-155 regulates tumor angiogenesis through both cancer cells and MDSC within tumors.
It is notable that our results on host miR155 deficiency and tumor growth differ from other recent studies [7, 8]. Differences in the tumor cell lines used that could change the accumulation of individual immune cell subsets in the tumor microenvironment may explain this discrepancy. The extent and modulation of major immune populations could vary in different tumor types and/or tumor stages. Thus, increased miR-155 could be a key player in balancing anti-and pro-tumor immune components within the tumor. In our given tumor model system, we provide clear evidence that miR-155 promotes tumor growth in an MDSC-dependent manner, as manifested via both “depletion” and “transfer” strategy in vivo.
Taken together, our study highlights the essence of evaluating the intrinsic role of miR-155 carefully in distinct immune cell subsets, where miR-155 could be either protective or deleterious to antitumor immunity. In this regard, it would be safe and important to develop the anti-miR-155 cancer therapy in cell-specific manner. It is becoming evident that miR-155 functions as “OncomiR” in concert with “ImmunomiR” in orchestrating cancer growth and progression.
Background The poor prognosis of sepsis warrants the investigation of biomarkers for predicting the outcome. Several studies have indicated that PANoptosis exerts a critical role in tumor initiation and development. Nevertheless, the role of PANoptosis in sepsis has not been fully elucidated. Methods We obtained Sepsis samples and scRNA-seq data from the GEO database. PANoptosis-related genes were subjected to consensus clustering and functional enrichment analysis, followed by identification of differentially expressed genes and calculation of the PANoptosis score. A PANoptosis-based prognostic model was developed. In vitro experiments were performed to verify distinct PANoptosis-related genes. An external scRNA-seq dataset was used to verify cellular localization. Results Unsupervised clustering analysis using 16 PANoptosis-related genes identified three subtypes of sepsis. Kaplan-Meier analysis showed significant differences in patient survival among the subtypes, with different immune infiltration levels. Differential analysis of the subtypes identified 48 DEGs. Boruta algorithm PCA analysis identified 16 DEGs as PANoptosis-related signature genes. We developed PANscore based on these signature genes, which can distinguish different PANoptosis and clinical characteristics and may serve as a potential biomarker. Single-cell sequencing analysis identified six cell types, with high PANscore clustering relatively in B cells, and low PANscore in CD16+ and CD14+ monocytes and Megakaryocyte progenitors. ZBP1, XAF1, IFI44L, SOCS1, and PARP14 were relatively higher in cells with high PANscore. Conclusion We developed a machine learning based Boruta algorithm for profiling PANoptosis related subgroups with in predicting survival and clinical features in the sepsis.
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Identity is a manifestation of our individual characteristics and intentions. It can be found in many different forms, spanning from physical features to abstract cultural elements. However identity is rarely a passive component of our lives, but rather a powerful tool we apply to make decisions or position ourselves in the society.
Through personal identity we express, we learn, we confront, we find others, we vote, we change, we hate and we love.
Can it be designed as a medium to empower people? Can it be used proactively to prepareusfor times ofuncertainty and hardship (for example in a global Pandemic)?
The bodily boundary objects are“soft speculations” extracted from anomalies of our New Normalcy. These are designed to engage with both general public and decision makers, attempting to offer a glimpse of how design can be used as a versatile tool to find common grounds within complex topics we are facing today, by expanding and adding depth, instead of simplifying and minimizing.
Abstract Activating the immune co-stimulatory receptor 4-1BB (CD137) with agonist antibody binding and crosslinking-inducing agents that elicit 4-1BB intracellular signaling potentiates the anti-tumor responses of CD8+ T cells. However, the underlying in-depth mechanisms remain to be defined. The type 2 adenosine receptors (primarily the high affinity receptor, A2AR) predominantly expressed on CD8+ T cells inhibit T cell activation and expansion by blocking TCR signaling in a cAMP-dependent manner. Here, we show that inactivation of the low affinity receptor A2BR rather than A2AR by continuous treatment of antagonists and/or genetic deletion induces superior survival advantage of effector CD8+ T cells with agonistic 4-1BB co-stimulation especially upon chronic TCR stimulation and/or long-term antigen exposure. Mechanistically, A2BR inactivation helps sustain the increased energy and biosynthetic requirements through the accumulation of intracellular glutathione (GSH) in response to agonistic 4-1BB co-stimulation. Importantly, A2BR inactivation in combination with agonistic 4-1BB co-stimulation displays a greater ability to modulate mitochondrial fitness for anti-tumor CD8+ T cell expansion while minimize T cell exhaustion. Thus, the A2BR pathway plays an unexpected role in metabolic reprogramming of GSH upon agonistic 4-1BB co-stimulation that allows the fine-tuning of the anti-tumor responses of CD8+ T cells. Supported by NCI CCSG P30 CA060553 R01CA258857
Posterior capsular opacification (PCO), the highest incidence complication after cataract surgery, is mainly due to the attachment, proliferation, and migration of the residual lens epithelial cells (LECs). Although the drug-eluting IOLs have been proved to be an effective way to prevent PCO incidence, its preparations are time consuming and require tedious preparation steps. Herein, the thermoreversible agarose is adopted to prepare drug-eluting IOL. Such functional coating can be obtained easily by simple immersion in the antiproliferative drug containing hot agarose and taken out for cooling, which not only does not affect the optical property but also can effectively decrease the PCO incidence after intraocular implantation. As a result, the proposed agarose coating provides a rapid and economical alternative of drug-eluting IOL fabrication for PCO prevention.
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