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Tumor microenvironment (TME) is emerging as an essential part of cervical cancer (CC) tumorigenesis and development, becoming a hotspot of research these years. However, comprehending the specific composition of TME is still facing enormous challenges, especially the immune and stromal components. In this study, we downloaded the RNA-seq profiles and somatic mutation data of 309 CC cases from The Cancer Genome Atlas (TCGA) database, which were analyzed by integrative bioinformatical methods. Initially, ESTIMATE computational method was employed to calculate the amount of immune and stromal components. Then, based on the high- and low-immunity cohorts, we recognized the differentially expressed genes (DEGs) as well as the differentially mutated genes (DMGs). Additionally, we conducted an intersection analysis of DEGs and DMGs, ultimately determining an immune-related prognostic signature, GTPase, IMAP Family Member 4 (GIMAP4). Moreover, sequential analyses demonstrated that GIMAP4 was a protective factor in CC, positively correlated with the overall survival (OS) and negatively with distant metastasis. Besides, we utilized the Gene Set Enrichment Analysis (GSEA) to explore the enrichment-pathways in high and low-expression cohorts of GIMAP4. The results indicated that the genes of the high-expression cohort had a high enrichment in immune-related biological processes and metabolic activities in the low one. Furthermore, CIBERSORT analysis was applied to evaluate the proportion of tumor-infiltrating immune cells (TICs), illustrating that several activated TICs were strongly associated with GIMAP4 expression, which suggested that GIMAP4 had the potential to be an indicator for the immune state in TME of CC. Hence, GIMAP4 contributed to predicting the CC patients’ clinical outcomes, such as survival rate, distant metastasis and immunotherapy response. Moreover, GIMAP4 could serve as a promising biomarker for TME remodeling, suggesting the possible underlying mechanisms of tumorigenesis and CC progression, which may provide different therapeutic perceptions of CC, and therefore improve treatment.

MicroRNAs play crucial roles in modulating immune system. miR-146a, a potent feedback suppressor of NF-κB signaling, was shown to limit the innate immune response and myelopoiesis in a knockout mouse model. Here, we observed high lymphopoiesis demonstrated as mild splenomegaly and severe lymphadenopathy in a miR-146a transgenic mouse model. Overexpression of miR-146a resulted in enhanced proliferation and reduced apoptosis of T cells. More activated CD4 T cells or effector memory T cells were observed in transgenic mice even under physiological conditions. Importantly, as one of the key steps to generate central tolerance, the positive selection of thymocytes is impaired in transgenic mice, resulting in more CD4 CD8 double-positive thymocytes but fewer CD4 CD8 and CD4 CD8 single-positive thymocytes. The maturation of selected CD4 CD8 thymocytes was also impaired, leading to more severe loss of CD4 CD8 than CD4 CD8 thymocytes in thymus of transgenic mice. Gene expression profiling analysis identified nine positive selection-associated genes, which were downregulated in transgenic mice, including genes encoding major histocompatibility complex class I/II molecules, IL-7 receptor α chain, and Gimap4, whose downregulation may contribute to the impairment of positive selection. Gimap4 was verified as a novel target of miR-146a. These findings further extend our understanding of the function of miR-146a in T cell biology and identify a novel regulatory mechanism underlying the positive selection during T cell development.

Polymorphisms within plant homeodomain finger protein 11 (PHF11) are associated with total IgE, allergic asthma and eczema. PHF11 is a transcriptional co‐activator of the Th1 effector cytokine genes, interleukin‐2 (IL2) and interferon‐γ (IFNG), co‐operating with nuclear factor kappa B (NF‐κB). The involvement with NF‐κB led us to test whether PHF11 might have a broader function in T‐cell activation and viability. We show that PHF11 is abundant in the cytoplasm of T‐cells and imported into the nucleus of activated T‐cells. Consistent with its presence in the nucleus, PHF11 was recruited to the IFNG promoter and over‐expression of PHF11 increased the binding of NF‐κB to the IFNG promoter and IFNG gene transcription. Over‐expression of PHF11 did not increase IL2 gene transcription, suggesting some specificity in promoter recognition. In contrast, small‐interfering RNA knock‐down of PHF11 decreased transcription of both IFNG and IL2 and led to decreased CD28 cell‐surface expression and reduced NF‐κB nuclear import and DNA binding. Knock‐down of PHF11 also decreased cell viability and was accompanied by reduced expression of GIMAP4 and 5 genes required for T‐cell differentiation, viability and homeostasis. Therefore, in addition to its earlier identified function in regulating Th1 cytokine gene expression, we now show that PHF11 has a broader function in contributing to T‐cell activation and viability.