Multiple Immune Cell Research Articles

Prognostic Significance of Glycolysis-Related Genes in Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LUSC) is one of the most common malignancies. There is growing evidence that glycolysis-related genes play a critical role in tumor development, maintenance, and therapeutic response by altering tumor metabolism and thereby influencing the tumor immune microenvironment. However, the overall impact of glycolysis-related genes on the prognostic significance, tumor microenvironment characteristics, and treatment outcome of patients with LUSC has not been fully elucidated. We used The Cancer Genome Atlas (TCGA) dataset to screen glycolysis-related genes with prognostic effects in LUSC and constructed signature and nomogram models using Lasso and Cox regression, respectively. In addition, we analyzed the immune infiltration and tumor mutation load of the genes in the models. We finally obtained a total of glycolysis-associated DEGs. The signature model and nomogram model had good prognostic power for LUSC. Gene expression in the models was highly correlated with multiple immune cells in LUSC. Through this analysis, we have identified and validated for the first time that glycolysis-related genes are highly associated with the development of LUSC. In addition, we constructed the signature model and nomogram model for clinical decision-making.

Identification of diagnostic signatures for ischemic stroke by machine learning algorithm

ObjectiveIschemic stroke (IS) is one of the major diseases threatening human health and survival and a leading cause of acquired mortality and disability in adults. The aim of this study was to screen diagnostic features of IS and to explore the characteristics of immune cell infiltration in IS pathogenesis. MethodsThe microarray data of IS (GSE16561, GSE58294, GSE37587, and GSE124026) in the GEO database were merged after removing the batch effect. Then integrated bioinformatic analysis and machine-learning strategies were adopted to analyze the functional correlation and select diagnostic signatures. The WGCNA was used to identify the co-expression modules related to IS. The CIBERSORT algorithm was performed to assess the inflammatory state of IS and to investigate the correlation between diagnostic signatures and infiltrating immune cells. ResultsFunctional analysis of dysregulated genes showed that immune response-regulating signaling pathway and pattern recognition receptor activity were enriched in the pathophysiology of IS. The turquoise module was identified as the significant module with IS. By using Lasso and SVM-RFE learning methods, we finally obtained four diagnostic genes, including LAMP2, CR1, CLEC4E, and F5. The corresponding results of AUC of ROC prediction model in training and validation cohort were 0.954 and 0.862, respectively. The immune cell infiltration analysis suggested that plasma cells, resting and activated NK cells, activated dendritic cells, memory B cells, CD8+ T cells, naïve CD4+ T cells, and resting mast cells may be involved in the development of IS. Additionally, these diagnostic signatures might be correlated with multiple immune cells in varying degrees. ConclusionWe identified four biologically relevant genes (LAMP2, CR1, CLEC4E, and F5) with diagnostic effects for IS, our results further provide novel insights regarding molecular mechanisms associated with various immune cells that related to IS for future investigations.

Endogenous retroviruses Suppressyn and Syncytin-2 as innovative prognostic biomarkers in Acute Myeloid Leukemia.

Emerging evidence has proven that human endogenous retroviruses (HERVs) play a critical role in the pathogenesis of Acute Myeloid Leukemia (AML), whereas the specific HERVs influencing the prognosis of AML patients have yet to be fully understood. In this study, a systematic exploration was achieved to identify potential prognostic HERVs for AML, sourced from TCGA and GTEx database. Differential analysis and functional enrichment studies were conducted using GO, KEGG, GSEA, and GSVA. The ESTIMATE algorithm was applied to explore the immune infiltration of HERVs in AML. A prognostic risk-score model was evaluated with predicted yearly accuracy using ROC analysis. Two HERVs Suppressyn and Syncytin-2, were identified as promising prognostic biomarkers, with high discrimination ability based on ROC analysis between AML and healthy cohorts from TCGA. Their expression was notably higher in AML patients compared to those in healthy individuals but correlates with favorable clinical outcomes in sub-groups such as white race, lower WBC counts, favorable and intermediate risks, and NPM1 or IDH1 mutation. Suppressyn and Syncytin-2 participated in immune-related pathways and exhibited correlations with multiple immune infiltration cells, such as T cells, mast cells, and tumor-associated macrophages. Finally, we developed a prognostic risk-scoring model combining Suppressyn and Syncytin-2, where a high risk-score is associated with better prognosis. Collectively, our findings revealed that Suppressyn and Syncytin-2 may act as valuable diagnostic and prognostic biomarkers for individuals with AML, while highlighting links between HERV activation, immunogenicity, and future therapeutic targets.

Spatial immune landscapes of SARS-CoV-2 gastrointestinal infection: macrophages contribute to local tissue inflammation and gastrointestinal symptoms.

In some patients, persistent gastrointestinal symptoms like abdominal pain, nausea, and diarrhea occur as part of long COVID-19 syndrome following acute respiratory symptoms caused by SARS-CoV-2. However, the characteristics of immune cells in the gastrointestinal tract of COVID-19 patients and their association with these symptoms remain unclear. Data were collected from 95 COVID-19 patients. Among this cohort, 11 patients who exhibited gastrointestinal symptoms and underwent gastroscopy were selected. Using imaging mass cytometry, the gastrointestinal tissues of these patients were thoroughly analyzed to identify immune cell subgroups and investigate their spatial distribution. Significant acute inflammatory responses were found in the gastrointestinal tissues, particularly in the duodenum, of COVID-19 patients. These alterations included an increase in the levels of CD68+ macrophages and CD3+CD4+ T-cells, which was more pronounced in tissues with nucleocapsid protein (NP). The amount of CD68+ macrophages positively correlates with the number of CD3+CD4+ T-cells (R = 0.783, p < 0.001), additionally, spatial neighborhood analysis uncovered decreased interactions between CD68+ macrophages and multiple immune cells were noted in NP-positive tissues. Furthermore, weighted gene coexpression network analysis was employed to extract gene signatures related to clinical features and immune responses from the RNA-seq data derived from gastrointestinal tissues from COVID-19 patients, and we validated that the MEgreen module shown positive correlation with clinical parameter (i.e., Total bilirubin, ALT, AST) and macrophages (R = 0.84, p = 0.001), but negatively correlated with CD4+ T cells (R = -0.62, p = 0.004). By contrast, the MEblue module was inversely associated with macrophages and positively related with CD4+ T cells. Gene function enrichment analyses revealed that the MEgreen module is closely associated with biological processes such as immune response activation, signal transduction, and chemotaxis regulation, indicating its role in the gastrointestinal inflammatory response. The findings of this study highlight the role of specific immune cell groups in the gastrointestinal inflammatory response in COVID-19 patients. Gene coexpression network analysis further emphasized the importance of the gene modules in gastrointestinal immune responses, providing potential molecular targets for the treatment of COVID-19-related gastrointestinal symptoms.

Sex- and time-dependent role of insulin regulated aminopeptidase in lipopolysaccharide-induced inflammation.

The enzyme, insulin regulated aminopeptidase (IRAP), is expressed in multiple immune cells such as macrophages, dendritic cells and T cells, where it plays a role in regulating the innate and adaptive immune response. There is a genetic association between IRAP and survival outcomes in patients with septic shock where a variant of its gene was found to be associated with increased 28-day mortality. This study investigated the role for IRAP in a lipopolysaccharide (LPS)-induced inflammatory response which is thought to model facets of the systemic inflammation observed in the early stages of human gram-negative sepsis. The frequencies and activation of splenic immune cell populations were investigated in the IRAP knockout (KO) mice compared to the wildtype controls over a period of 4-, 24-, or 48-hours following LPS stimulation. Dendritic cells isolated from the spleen of female IRAP KO mice, displayed significant increases in the activation markers CD40, CD86 and MHCII at 24 hours after LPS induction. A modest heightened pro-inflammatory response to LPS was observed with increased expression of activation marker CD40 in M1 macrophages from male IRAP knockout mice. Observations in vitro in bone marrow-derived macrophages (BMDM) revealed a heightened pro-inflammatory response to LPS with significant increases in the expression of CD40 in IRAP deficient cells compared with BMDM from WT mice. The heightened LPS-induced response was associated with increased pro-inflammatory cytokine secretion in these BMDM cells. A genotype difference was also detected in the BMDM from female mice displaying suppression of the LPS-induced increases in the activation markers CD40, CD86, CD80 and MHCII in IRAP deficient cells. Thus, this study suggests that IRAP plays specific time- and sex-dependent roles in the LPS-induced inflammatory response in dendritic cells and macrophages.

Identification of MDK as a Hypoxia- and Epithelial-Mesenchymal Transition-Related Gene Biomarker of Glioblastoma Based on a Novel Risk Model and In Vitro Experiments.

Tumor cells are commonly exposed to a hypoxic environment, which can easily induce the epithelial-mesenchymal transition (EMT) of tumor cells, further affecting tumor proliferation, invasion, metastasis, and drug resistance. However, the predictive role of hypoxia and EMT-related genes in glioblastoma (GBM) has not been investigated. Intersection genes were identified by weighted correlation network analysis (WGCNA) and differential expression analyses, and a risk model was further constructed by LASSO and Cox analyses. Clinical, immune infiltration, tumor mutation, drug treatment, and enrichment profiles were analyzed based on the risk model. The expression level of the MDK gene was tested using RT-PCR, immunohistochemistry, and immunofluorescence. CCK8 and EdU were employed to determine the GBM cells' capacity for proliferation while the migration and invasion ability were detected by a wound healing assay and transwell assay, respectively. Based on the GBM data of the TCGA and GTEx databases, 58 intersection genes were identified, and a risk model was constructed. The model was verified in the CGGA cohort, and its accuracy was confirmed by the ROC curve (AUC = 0.807). After combining clinical subgroups, univariate and multivariate Cox regression analyses showed that risk score and age were independent risk factors for GBM patients. Furthermore, our subsequent analysis of immune infiltration, tumor mutation, and drug treatment showed that risk score and high- and low-risk groups were associated with multiple immune cells, mutated genes, and drugs. Enrichment analysis indicated that the differences between high- and low-risk groups were manifested in tumor-related pathways, including the PI3K-AKT and JAK-STAT pathways. Finally, in vivo experiments proved that the hypoxia environment promoted the expression of MDK, and MDK knockdown reduced the proliferation, migration, and EMT of GBM cells induced by hypoxia. Our novel prognostic correlation model provided more potential treatment strategies for GBM patients.

Assessing immune hepatotoxicity of troglitazone with a versatile liver-immune-microphysiological-system.

Drug-induced liver injury is a prevalent adverse event associated with pharmaceutical agents. More significantly, there are certain drugs that present severe hepatotoxicity only during the clinical phase, consequently leading to the termination of drug development during clinical trials or the withdrawal from the market after approval. The establishment of an evaluation model that can sensitively manifest such hepatotoxicity has always been a challenging aspect in drug development. In this study, we build a liver-immune-microphysiological-system (LIMPS) to fully demonstrate the liver injury triggered by troglitazone (TGZ), a drug that was withdrawn from the market due to hepatotoxicity. Leveraging the capabilities of organ-on-chip technology allows for the dynamic modulation of cellular immune milieu, as well as the synergistic effects between drugs, hepatocytes and multiple immune cells. Through the LIMPS, we discovered that 1) TGZ can promote neutrophils to adhered hepatocytes, 2) the presence of TGZ enhances the crosstalk between macrophages and neutrophils, 3) the induction of damage in hepatocytes by TGZ at clinically relevant blood concentrations not observed in other in vitro experiments, 4) no hepatotoxicity was observed in LIMPS when exposed to rosiglitazone and pioglitazone, structurally similar analogs of TGZ, even at the higher multiples of blood drug concentration levels. As an immune-mediated liver toxicity assessment method, LIMPS is simple to operate and can be used to test multiple drug candidates to detect whether they will cause severe liver toxicity in clinical settings as early as possible.

Comprehensive Analysis of Key Endoplasmic Reticulum Stress-Related Genes and Immune Infiltrates in Stanford Type A Aortic Dissection.

Type A aortic dissection is a fatal disease. However, the role of endoplasmic reticulum stress-related genes (ERSRGs) in type A aortic dissection has not yet been fully clarified. Differentially expressed genes in the aorta of type A aortic dissection patients were analyzed based on the GSE52093 database. The ERSRGs were downloaded from the GeneCards website. Functional enrichment analysis and protein-protein interaction analysis were performed on the acquired differentially expressed ERSRGs. The mRNA expression of the 5 top key differentially expressed ERSRGs was further explored in GSE153434 and clinical samples. Immune infiltration correlation analysis was performed on the validated key genes. Finally, we constructed regulatory networks of transcription factors, miRNAs, and chemicals. Twelve differentially expressed ERSRGs were identified, of which 8 genes were downregulated and 4 genes were upregulated. GeneMANIA was adopted to analyze these genes and their interacting proteins, and the results showed that the main function was calcium ion transport. Four key genes, ACTC1, CASQ2, SPP1, and REEP1, were validated in GSE153434 and clinical samples. The area under the ROC curve values for ACTC1, CASQ2, SPP1, and REEP1 were 0.92, 0.96, 0.89, and 1.00, respectively. ACTC1 and REEP1 correlated with multiple immune cells. Many transcription factors, microRNAs, and chemicals were identified with the potential to regulate these 4 key genes. In this study, we identified 12 differentially expressed ERSRGs by analyzing the Gene Expression Omnibus database. Four key genes may influence the development of type A aortic dissection by regulating endoplasmic reticulum stress. These results expand our understanding of type A aortic dissection, and the 4 key genes are expected to be diagnostic markers and potential therapeutic targets.

Prognostic significance of LRPPRC and its association with immune infiltration in liver hepatocellular carcinoma.

Leucine rich pentatricopeptide repeat containing (LRPPRC) protein is a multifunctional protein involved in cell cycle progression and tumor development. However, its prognostic significance and association with immune infiltration in Liver hepatocellular carcinoma (LIHC) remain unclear. We utilized transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases of LIHC patients to investigate the potential pro-cancer role of LRPPRC, including differential expression of LRPPRC in LIHC, prognostic value, clinicopathological features, immune cell infiltration relevance and function enrichment analysis. Our findings suggest that LRPPRC is upregulated in LIHC and exhibits correlations with survival, clinical stage, and tumor grade in LIHC patients. Additionally, immune infiltration analysis revealed significant negative correlations between LRPPRC expression and multiple tumor-infiltrating immune cells, including CTLs, DCs, pDCs, B cells, Th17 cells, neutrophils, T cells, Mast cells, Th1 cells, Tregs, and NK cells, whereas a significant positive correlation was observed with infiltration of Th2 cells, T helper cells and Tcms. Furthermore, functional enrichment analysis indicated that LRPPRC may be involved in G2m checkpoint, mitotic spindle, E2f targets, Wnt Beta catenin signaling, spermatogenesis and other processes.

Study of LY9 as a potential biomarker for prognosis and prediction of immunotherapy efficacy in lung adenocarcinoma.

Lymphocyte antigen 9 (LY9) participates in the development of several tumors and diseases but has not been reported yet in lung adenocarcinoma (LUAD). First, we analyzed the expression and prognostic value of LY9 in pan-cancer, including LUAD. Additionally, we conducted a correlation analysis of LY9 expression in LUAD with immune cell infiltration using the TIMER database and the CIBERSORT algorithm, and with immune checkpoints using the GEPIA database. Also, we constructed a potential ceRNA network for LY9. Furthermore, we explored LY9-related pathways by Gene Set Enrichment Analysis (GSEA). Finally, validation of differential expression at the mRNA level was obtained from the GEO database. We collected LUAD tissues for Quantitative Real-time PCR (qRT-PCR) to verify the expression of LY9, CD8, and CD4 and calculated the correlation between them. We also conducted immunohistochemistry (IHC) to verify the protein expression of LY9. Results showed that LY9 was highly expressed in various tumors, including LUAD. Besides, patients with high LY9 expression presented longer overall survival (OS) and more multiple lymphocyte infiltrations. The expression of LY9 in LUAD strongly and positively correlates with multiple immune cell infiltration and immune checkpoints. The functional enrichment analysis indicated that LY9 was involved in multiple immune-related pathways and non-small cell lung cancer. Moreover, a ceRNA regulatory network of LINC00943-hsa-miR-141-3p-LY9 might be involved. Finally, GSE68465 dataset confirmed differential expression of LY9 mRNA levels in LUAD and the qRT-PCR results verified LY9 had a strong and positive correlation with CD4 and CD8 T cells. Unfortunately, IHC did not detect the expression of LY9 protein level in tumor tissues and WB experiments validated the protein expression of LY9 in the OCI-AML-2 cell line. Therefore, we hypothesized that LY9 could serve as a potential, novel prognostic biomarker for LUAD and could predict immunotherapy efficacy at the mRNA level.

CTLA4 expression profiles and their association with clinical outcomes of breast cancer: a systemic review.

The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is involved in the progression of various cancers, but its biological roles in breast cancer (BRCA) remain unclear. Therefore, we performed a systematic multiomic analysis to expound on the prognostic value and underlying mechanism of CTLA4 in BRCA. We assessed the effect of CTLA4 expression on BRCA using a variety of bioinformatics platforms, including Oncomine, GEPIA, UALCAN, PrognoScan database, Kaplan-Meier plotter, and R2: Kaplan-Meier scanner. CTLA4 was highly expressed in BRCA tumor tissue compared to normal tissue (P < 0.01). The CTLA4 messenger RNA levels in BRCA based on BRCA subtypes of Luminal, human epidermal growth factor receptor 2, and triple-negative BRCA were considerably higher than in normal tissues (P < 0.001). However, the overexpression of CTLA4 was associated with a better prognosis in BRCA (P < 0.001) and was correlated with clinicopathological characteristics including age, T stage, estrogen receptors, progesterone receptors, and prediction analysis of microarray 50 (P < 0.01). The infiltration of multiple immune cells was associated with increased CTLA4 expression in BRCA (P < 0.001). CTLA4 was highly enriched in antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. This study provides suggestive evidence of the prognostic role of CTLA4 in BRCA, which may be a therapeutic target for BRCA. Furthermore, CTLA4 may influence BRCA prognosis through antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. These findings help us understand how CTLA4 plays a role in BRCA and set the stage for more research.

Differential expression profiles and functional prediction of circular RNAs in lung cancer patients with chronic obstructive pulmonary disease: a pilot study.

Chronic obstructive pulmonary disease (COPD), characterized by clinical sub-phenotypes such as emphysema (E) and chronic bronchitis (CB), is associated with a greater risk of lung cancer (LC). This study aimed to assess the expression patterns of circRNA and their potential functional involvement in LC patients with COPD. A circRNA microarray was used to characterize differentially expressed circRNAs (DEcircRNAs) profiles. A total of 176, 240, 163, and 243 DEcircRNAs were identified in comparisons between CB vs. LC patients (Con), E vs. Con, E vs. CB, and CBE vs. Con, respectively. DEcircRNAs in all comparison groups were primarily associated with immune-related GO terms and were also enriched in immune and inflammatory pathways. In total, 49 DEcircRNAs were significantly correlated with the infiltration of multiple immune cells. Among them, hsa-MROH9_0001 and hsa-RP11-35J10_0013 were positively and negatively correlated with plasma cells and T-cell CD4 memory resting cells, respectively; these two DEcircRNA-sponged miRNAs have good diagnostic performance. WGCNA identified six key circRNAs associated with CB progression. The expression patterns of hsa-MROH9_0001 and circRNA_21729 in E and CB groups were confirmed by RT-qPCR. In conclusion, we reported circRNA profiles and the findings demonstrated that hsa-MROH9_0001 and circRNA_21729 may be potential therapeutic targets for LC with COPD.

The Impact of Tobacco Smoking on Systemic Sclerosis, Idiopathic Inflammatory Myositis, and Systemic Lupus Erythematosus.

This narrative review aims specifically to explore the relationship between tobacco exposure and systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), and systemic lupus erythematosus (SLE). Relevant articles were obtained by searching key terms such as "tobacco," "smoking," "scleroderma," "myositis," "lupus," and "Sjögren's" in PubMed and Google Scholar databases. The selected articles ranged from the years 2010 to 2023. Inclusion criteria were based on the relevance and contribution to the field of study. Systemic sclerosis is a complex condition involving multiple immune cell lines that can be influenced by tobacco. However, the existing literature does not provide sufficient evidence to support an increased risk of SSc in smokers or the impact on treatment options. Cigarette smoking does increase the risk of skin ulcerations in SSc patients. In addition, cigarette smoking has been associated with IIM through genetic and molecular mechanisms. Smokers with dermatomyositis or polymyositis are at an elevated risk of atherosclerosis and interstitial lung disease. Similarly, smoking in patients with SLE increases the risk of organ damage, thrombosis, and disease severity compared with non-smokers. Smokers with SLE also have more difficulty in controlling disease flares compared with non-smokers. Tobacco exposure can lead to secondary complications in patients with IIM and SLE, although the course of treatment may not differ significantly. No definitive conclusions can be drawn to the clear relationship between tobacco smoking and Sjögren's's syndrome.

Comprehensive analysis of prognostic value and immune infiltration of Regulator of Chromosome Condensation 2 in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) incidence and mortality take the leading place of most malignancies. Previous studies have revealed the regulator of chromosome condensation 1 (RCC1) family members played an essential role during tumorigenesis. However, its biological functions in LUAD still need further investigation. Methods: Several databases were applied to explore potential effects of RCC1 family members on LUAD, such as Oncomine, GEPIA, and cBioPortal. Real-time PCR and immunohistochemistry were used to verify the expression of RCC2 in stage I LUAD. H1975 and A549 were selected to explore the biological function of RCC2 in cellular malignant phenotype. Results: The expressions of RCC1 and RCC2 showed marked differences in malignant tissue compared to lung tissue. The higher the expression levels of RCC1 or RCC2 in LUAD patients, the shorter their overall survival (OS). In normal lung tissues, RCC1 expression was highly enriched in alveolar cells and endothelial cells. Compare with RCC1, RCC2 expression in normal lung tissue was significantly enriched in macrophages, B cells and granulocytes. Additionally, RCC2 expression level was correlated with multiple immune cell infiltration in LUAD. Moreover, the mutation or different sCNA status of RCC2 exerted influence on multiple immune cell infiltration distribution. We found that the upregulation of RCC1 and RCC2 were obviously related to TP53 mutation. GSEA analysis revealed that RCC2 was involved in the process of DNA replication, nucleotide excision repair and cell cycle, which might affect tumor progression through P53 signaling pathway. We further elucidated that downregulation of RCC2 could dramatically repress the migration and invasion of LUAD cells. Conclusions: The study demonstrated that RCC1 and RCC2 expression were markedly increased in early-stage of LUAD. Patients with high expression of RCC1 or RCC2 had a worse prognosis. Based on our analysis, RCC1 and RCC2 might exert influence on LUAD process through DNA replication, nucleotide excision repair and cell cycle, as well as cells migration and invasion. Different from RCC1, RCC2 also involved in immune infiltration. These analyses provided a novel insight into the identification of diagnostic biomarker.

Single-Cell Sequencing Combined with Transcriptome Sequencing Constructs a Predictive Model of Key Genes in Multiple Sclerosis and Explores Molecular Mechanisms Related to Cellular Communication.

Multiple sclerosis (MS) causes chronic inflammation and demyelination of the central nervous system and comprises a class of neurodegenerative diseases in which interactions between multiple immune cell types mediate the involvement of MS development. However, the early diagnosis and treatment of MS remain challenging. Gene expression profiles of MS patients were obtained from the Gene Expression Omnibus (GEO) database. Single-cell and intercellular communication analyses were performed to identify candidate gene sets. Predictive models were constructed using LASSO regression. Relationships between genes and immune cells were analyzed by single sample gene set enrichment analysis (ssGSEA). The molecular mechanisms of key genes were explored using gene enrichment analysis. An miRNA network was constructed to search for target miRNAs related to key genes, and related transcription factors were searched by transcriptional regulation analysis. We utilized the GeneCard database to detect the correlations between disease-regulated genes and key genes. We verified the mRNA expression of 4 key genes by reverse transcription-quantitative PCR (RT‒qPCR). Monocyte marker genes were selected as candidate gene sets. CD3D, IL2RG, MS4A6A, and NCF2 were found to be the key genes by LASSO regression. We constructed a prediction model with AUC values of 0.7569 and 0.719. The key genes were closely related to immune factors and immune cells. We explored the signaling pathways and molecular mechanisms involving the key genes by gene enrichment analysis. We obtained and visualized the miRNAs associated with the key genes using the miRcode database. We also predicted the transcription factors involved. We used validated key genes in MS patients, several of which were confirmed by RT‒qPCR. The prediction model constructed with the CD3D, IL2RG, MS4A6A, and NCF2 genes has good diagnostic efficacy and provides new ideas for the diagnosis and treatment of MS.

Spatial multi-omics analysis of the microenvironment in traumatic spinal cord injury: a narrative review.

Traumatic spinal cord injury (tSCI) is a severe injury to the central nervous system that is categorized into primary and secondary injuries. Among them, the local microenvironmental imbalance in the spinal cord caused by secondary spinal cord injury includes accumulation of cytokines and chemokines, reduced angiogenesis, dysregulation of cellular energy metabolism, and dysfunction of immune cells at the site of injury, which severely impedes neurological recovery from spinal cord injury (SCI). In recent years, single-cell techniques have revealed the heterogeneity of multiple immune cells at the genomic, transcriptomic, proteomic, and metabolomic levels after tSCI, further deepening our understanding of the mechanisms underlying tSCI. However, spatial information about the tSCI microenvironment, such as cell location and cell-cell interactions, is lost in these approaches. The application of spatial multi-omics technology can solve this problem by combining the data obtained from immunohistochemistry and multiparametric analysis to reveal the changes in the microenvironment at different times of secondary injury after SCI. In this review, we systematically review the progress of spatial multi-omics techniques in the study of the microenvironment after SCI, including changes in the immune microenvironment and discuss potential future therapeutic strategies.

Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation.

Tumor immune microenvironment (TIME) is a tiny structure that contains multiple immune cell components around tumor cells, which plays an important role in tumorigenesis, and is also the potential core area of activated immunotherapy. How immune cells with tumor-killing capacity in TIME are hijacked by tumor cells during the progression of tumorigenesis and transformed into subpopulations that facilitate cancer advancement is a question that needs to be urgently addressed nowadays. γδ T cells (their T cell receptors are composed of γ and δ chains), a unique T cell subpopulation distinguished from conventional αβ T cells, are involved in a variety of immune response processes through direct tumor-killing effects and/or indirectly influencing the activity of other immune cells. However, the presence of γδ T cells in the tumor microenvironment (TME) has been reported to be associated with poor prognosis in some tumors, suggesting that certain γδ T cell subsets may also have pro-tumorigenic effects. Recent studies have revealed that metabolic pathways such as activation of glycolysis, increase of lipid metabolism, enhancement of mitochondrial biosynthesis, alterations of fatty acid metabolism reshape the local TME, and immune cells trigger metabolic adaptation through metabolic reprogramming to meet their own needs and play the role of anti-tumor or immunosuppression. Combining previous studies and our bioinformatics results, we hypothesize that γδT cells compete for resources with hepatocellular carcinoma (HCC) cells by means of fatty acid metabolic regulation in the TME, which results in the weakening or loss of their ability to recognize and kill HCC cells through genetic and epigenetic alterations, thus allowing γδT cells to be hijacked by HCC cells as a subpopulation that promotes HCC progression.

Advances in methodologies for evaluating cell-mediated immune responses

Cell-mediated immune response is an important part of machinery in maintaining the body's homeostasis. After the innate immune system selectively activates the adaptive immune system, the cell-mediated immunity exerts its killing and clearance functions. Therefore, evaluating the level of cell-mediated immune response is crucial in the diagnosis and treatment of cancer, monitoring the immune status after organ transplantation, diagnosing and preventing viral diseases, and evaluating the effectiveness of vaccines and other areas. From the initial overall assessment of the immune effects in vivo to the precise detection of the number and function of multiple immune cells, the evaluation methods of cell-mediated immune response have greatly advanced. However, cell-mediated immune response involves multiple levels in the body, and it's difficult to choose the numerous detection methods available. The article systematically compares the evaluation methods of cell-mediated immune response at four different levels: the organism, the tissue and organ, the immune cells and the immune molecules, with the aim to facilitate the applications of related technologies.

Neutrophil infiltration associated genes on the prognosis and tumor immune microenvironment of lung adenocarcinoma.

The neutrophils exhibit both anti-tumor and pro-tumor effects in cancers. The correlation between neutrophils and tumor development in lung adenocarcinoma (LUAD) is still uncertain, possibly due to a lack of specific neutrophil infiltration evaluation methods. In this study, we identified 30 hub genes that were significantly associated with neutrophil infiltration in LUAD through data mining, survival analysis, and multiple tumor-infiltrating immune cells (TICs) analysis, including TIMER, CIBERSORT, QUANTISEQ, XCELL, and MCPCOUNTER. Consensus clustering analysis showed that these 30 hub genes were correlated with clinical features in LUAD. We further developed a neutrophil scoring system based on these hub genes. The neutrophil score was significantly correlated with prognosis and tumor immune microenvironment (TIME) in LUAD. It was also positively associated with PD-L1 expression and negatively associated with tumor mutational burden (TMB). When combined with the neutrophil score, the predictive capacity of PD-L1 and TMB for prognosis was significantly improved. Thus, the 30 hub genes might play an essential role in the interaction of neutrophils and LUAD, and the neutrophil scoring system might effectually assess the infiltration of neutrophils. Furthermore, we verified the expression of these 30 genes in the LUAD tumor tissues collected from our department. We further found that overexpressed TNFAIP6 and TLR6 and downregulated P2RY13, SCARF1, DPEP2, PRAM1, CYP27A1, CFP, GPX3, and NCF1 in LUAD tissue might be potentially associated with neutrophils pro-tumor effects. The following in vitro experiments demonstrated that TNFAIP6 and TLR6 were significantly overexpressed, and P2RY13 and CYP27A1 were significantly downregulated in LUAD cell lines, compared to BEAS-2B cells. Knocking down TNFAIP6 in A549 and PC9 resulted in the upregulation of FAS, CCL3, and ICAM-1, and the downregulation of CCL2, CXCR4, and VEGF-A in neutrophils when co-culturing with the conditioned medium (CM) from LUAD cells. Knocking down TNFAIP6 in LUAD also led to an elevated early apoptosis rate of neutrophils. Therefore, overexpressed TNFAIP6 in LUAD cancer cells might lead to neutrophils "N2" polarization, which exhibited pro-tumor effects. Further research based on the genes identified in this pilot study might shed light on neutrophils' effects on LUAD in the future.

Neutrophils-biology and diversity.

Neutrophils, the most abundant white blood cells in the human circulation, play crucial roles in various diseases, including kidney disease. Traditionally viewed as short-lived pro-inflammatory phagocytes that release reactive oxygen species, cytokines and neutrophil extracellular traps, recent studies have revealed their complexity and heterogeneity, thereby challenging this perception. Neutrophils are now recognized as transcriptionally active cells capable of proliferation and reverse migration, displaying phenotypic and functional heterogeneity. They respond to a wide range of signals and deploy various cargo to influence the activity of other cells in the circulation and in tissues. They can regulate the behavior of multiple immune cell types, exhibit innate immune memory, and contribute to both acute and chronic inflammatory responses while also promoting inflammation resolution in a context-dependent manner. Here, we explore the origin and heterogeneity of neutrophils, their functional diversity, and the cues that regulate their effector functions. We also examine their emerging role in infectious and non-infectious diseases with a particular emphasis on kidney disease. Understanding the complex behavior of neutrophils during tissue injury and inflammation may provide novel insights, thereby paving the way for potential therapeutic strategies to manage acute and chronic conditions. By deciphering their multifaceted role, targeted interventions can be developed to address the intricacies of neutrophil-mediated immune responses and improve disease outcomes.