Transcriptome analysis reveals the clinical significance of CXCL13 in Pan-Gyn tumors.

BACKGROUND: Gynecologic and breast tumors (Pan-Gyn) exhibit similar characteristics, and the role of CXCL13 in anti-tumor immunity and it's potential as a biomarker for immune checkpoint blockade (ICB) therapy have been gradually revealed. However, the precise role of CXCL13 in Pan-Gyn remains unclear, lacking a systematic analysis. METHODS: We analyzed 2497 Pan-Gyn samples from the TCGA database, categorizing them into high and low CXCL13 expression groups. Validation was conducted using tumor expression datasets sourced from the GEO database. Correlation between CXCL13 and tumor immune microenvironment (TIME) was evaluated using multiple algorithms. Finally, we established nomograms for 3-year and 5-year mortality. RESULTS: High expression of CXCL13 in Pan-Gyn correlates with a favorable clinical prognosis, increased immune cell infiltration, and reduced intra-tumor heterogeneity. Model was assessed using the C-index [BRCA: 0.763 (0.732-0.794), UCEC: 0.821 (0.793-0.849), CESC: 0.736 (0.684-0.788), and OV: 0.728 (0.707-0.749)], showing decent prediction of discrimination and calibration. CONCLUSION: Overall, this study provides comprehensive insights into the commonalities and differences of CXCL13 in Pan-Gyn, potentially opening new avenues for personalized treatment.

A distinct tumor microenvironment makes anaplastic thyroid cancer more lethal but immunotherapy sensitive than papillary thyroid cancer.

Both anaplastic thyroid cancer (ATC) and papillary thyroid cancer (PTC) originate from thyroid follicular epithelial cells, but ATC has a significantly worse prognosis and shows resistance to conventional therapies. However, clinical trials found that immunotherapy works better in ATC than late-stage PTC. Here, we used single-cell RNA sequencing (scRNA-Seq) to generate a single-cell atlas of thyroid cancer. Differences in ATC and PTC tumor microenvironment components (including malignant cells, stromal cells, and immune cells) leading to the polarized prognoses were identified. Intriguingly, we found that CXCL13+ T lymphocytes were enriched in ATC samples and might promote the development of early tertiary lymphoid structure (TLS). Last, murine experiments and scRNA-Seq analysis of a treated patient's tumor demonstrated that famitinib plus anti-PD-1 antibody could advance TLS in thyroid cancer. We displayed the cellular landscape of ATC and PTC, finding that CXCL13+ T cells and early TLS might make ATC more sensitive to immunotherapy.

CXC ligand 13 orchestrates an immunoactive microenvironment and enhances immunotherapy response in head and neck squamous cell carcinoma.

Objectives: This study aims to systematically explore the role of chemokine CXC ligand 13 (CXCL13) in head and neck squamous cell carcinoma (HNSCC). Methods: The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases provided the RNA-seq data for cancer and normal tissues, respectively. Gene set enrichment analysis was applied to search the cancer hallmarks associated with CXCL13 expression. TIMER2.0 was the main platform used to investigate the immune cell infiltration related to CXCL13. Immunohistochemistry was applied to explore the relationship between CXCL13 and patients' prognosis and the relationship between CXCL13 and tertiary lymphoid structures (TLSs). Results: The expression of CXCL13 was upregulated in most tumors, including HNSCC. The higher expression of CXCL13 was closely related to the positive prognosis of HNSCC. CXCL13 was mainly expressed in B cells and CD8 + T cells, revealing the relationship between its expression and immune activation in the tumor microenvironment. Furthermore, immunohistochemistry and multiple fluorescence staining analysis of HNSCC samples showed a powerful correlation between CXCL13 expression, TLSs formation, and positive prognosis. Finally, CXCL13 significantly increased the response to cancer immunotherapy. Conclusions: CXCL13 may function as a potential biomarker for predicting prognosis and immunotherapy response and associate with TLSs in HNSCC.

CT-based radiomics prediction of CXCL13 expression in ovarian cancer.

BACKGROUND: Ovarian cancer, the most common malignancy in the female reproductive system, and patients tend to be at middle and advanced clinical stages when diagnosed. Therefore, early detection and early diagnosis have important clinical significance for the treatment of ovarian cancer patients. CXCL13, a chemokine with the ligands CXCR3 and CXCR5, is involved in the tumor metastasis process. PURPOSE: This study aimed to predict mRNA expression of CXCL13 in ovarian cancer tissues noninvasively. METHODS: Medical imaging data and transcriptomic sequencing data of the 343 ovarian cancer patients were downloaded from the TCIA and TCGA databases, respectively. Seventy-six radiomics features were extracted from the CT data. Seven features were selected for model construction by using logistic regression. Accuracy, specificity, sensitivity, positive predictive value, and negative predictive value were used to evaluate the radiomics model. RESULTS: High CXCL13 expression was found to be a significant protective factor for OS [HR (95% CI) = 0.755 (0.622-0.916), p = 0.004]. There was a significant positive correlation between CXCL13 and the degree of eosinophil infiltration. A calibration curve and the Hosmer-Lemeshow goodness-of-fit test showed that the prediction probability of the radiomics prediction model for high expression of CXCL13 was consistent with the true value. The AUC value of the nomogram model's ability to predict OS (12 months) was 0.758. The calibration plot and DCA both showed high clinical applicability for the nomogram model. CONCLUSION: CXCL13 is a candidate predictive biomarker for OC and correlates with the degree of plasma cell and eosinophil infiltration.

Repetitive mRNA vaccination is required to improve the quality of broad-spectrum anti-SARS-CoV-2 antibodies in the absence of CXCL13.

Since the initial spread of severe acute respiratory syndrome coronavirus 2 infection, several viral variants have emerged and represent a major challenge for immune control, particularly in the context of vaccination. We evaluated the quantity, quality, and persistence of immunoglobulin G (IgG) and IgA in individuals who received two or three doses of messenger RNA (mRNA) vaccines, compared with previously infected vaccinated individuals. We show that three doses of mRNA vaccine were required to match the humoral responses of preinfected vaccinees. Given the importance of antibody-dependent cell-mediated immunity against viral infections, we also measured the capacity of IgG to recognize spike variants expressed on the cell surface and found that cross-reactivity was also strongly improved by repeated vaccination. Last, we report low levels of CXCL13, a surrogate marker of germinal center activation and formation, in vaccinees both after two and three doses compared with preinfected individuals, providing a potential explanation for the short duration and low quality of Ig induced.

CXCL13 variant predicts pegylated-interferon α treatment response in HBeAg-positive chronic hepatitis B patients.

As a key immune cytokine, C-X-C motif chemokine ligand 13 (CXCL13) has been reported to play critical roles in immune control of hepatitis B virus (HBV) infection. We aimed to screen single-nucleotide polymorphisms (SNPs) of CXCL13 for predicting response to pegylated interferon-alpha (PegIFNα) therapy of chronic hepatitis B (CHB) patients. Two independent cohorts with a total of 945 (Cohort 1, n = 238; Cohort 2, n = 707) hepatitis B e antigen (HBeAg)-positive CHB patients treated with PegIFNα were enrolled in this retrospective cohort study. Eight candidate SNPs were selected through gene-wide SNP mining within or flanking CXCL13. A polygenic score (PGS) was utilized to assess the cumulative effects of multiple SNPs. The associations of candidate SNPs and PGS with combined response (CR, defined as the combination of HBeAg seroconversion and HBV DNA level <3.3log10 IU/mL) and hepatitis B surface antigen (HBsAg) level were evaluated. Among the eight candidate SNPs, rs76084459 which is located at upstream of CXCL13 was significantly associated with both CR (p = 0.002) and HBsAg level (p = 0.015). A PGS integrating CXCL13_rs76084459 and five other SNPs, which were previously identified as predictors of PegIFNα treatment response, was further strongly correlated with CR (p = 1.759 × 10-10 ) and HBsAg level (p = 0.004). This study demonstrated that CXCL13_rs76084459 can predict response to PegIFNα treatment of HBeAg-positive CHB patients. A PGS composed of six SNPs including CXCL13_rs76084459 predicts PegIFNα treatment response better.

Tfl deletion induces extraordinary Cxcl13 secretion and cachexia in VavP-Bcl2 transgenic mice.

STATEMENT OF SIGNIFICANCE: Loss of TFL, found in several types of lymphoma, induces excessive CXCL13 secretion through RNA dysregulation contributing to body weight loss and early death in lymphoma model mice. Follicular lymphoma (FL) is associated with overexpressed BCL-2 and other genetic aberrations, including 6q-. We identified a novel gene on 6q25, "Transformed follicular lymphoma (TFL)," from a transformed FL. TFL regulates several cytokines via mRNA degradation, which has been suggested to underlie resolving inflammation. Fluorescence in situ hybridization revealed a deletion of TFL occurred in 13.6% of various B-cell lymphoma samples. We developed VavP-bcl2 transgenic, TFL deficit mice (Bcl2-Tg/Tfl -/-) to seek how TFL affects disease progression in this lymphoma model. While Bcl2-Tg mice developed lymphadenopathy and died around 50 weeks, Bcl2-Tg/Tfl -/- mice lost body weight around 30 weeks and died about 20 weeks earlier than Bcl2-Tg mice. Furthermore, we found a unique B220-IgM+ cell population in the bone marrow of Bcl2-Tg mice. cDNA array in this population revealed that Cxcl13 mRNA in Bcl2-Tg/Tfl -/- mice expressed significantly higher than Bcl2-Tg mice. In addition, bone marrow extracellular fluid and serum showed an extremely high Cxcl13 concentration in Bcl2-Tg/Tfl -/- mice. Among bone marrow cells, the B220-IgM+ fraction was the main producer of Cxcl13 in culture. A reporter assay demonstrated TFL regulates CXCL-13 via induction of 3'UTR mRNA degradation in B lineage cells. These data suggest Tfl regulates Cxcl13 in B220-IgM+ cells in the bone marrow, and a very high concentration of serum Cxcl13 arising from these cells may contribute to early death in lymphoma-bearing mice. Since several reports have suggested the association of CXCL13 expression with lymphoma, these findings provide new insights into cytokine regulation via TFL in lymphoma.

Long non-coding RNA maternally expressed gene 3, miR-125a-5p, CXCL13, and NF-kB in patients with immune thrombocytopenia.

The main aim of this study was to assess the expression level of circulating long non-coding RNA maternally expressed gene 3 (lncRNA-MEG3), microRNA (miR-125a-5P), the chemokine C-X-C motif ligand13 (CXCL13), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in immune thrombocytopenia (ITP) cases and to study its relation to the disease severity and treatment response. This case-control study included 45 patients newly diagnosed as ITP and 45 healthy subjects. We assessed complete blood count, antinuclear antibodies, hepatitis B and C virus serology, lncRNA-MEG3, miR-125a-5P, and CXCL13 expression in serum by real-time PCR and NF-kb protein by ELISA. In ITP patients compared to control, lncRNA-MEG3 was significantly increased, and miRNA-125a-5P was decreased, and this was associated with higher CXCL13 and NF-kB levels (P < 0.001, for all).There was a significant negative correlation between platelet count and lncRNA-MEG3, CXCL13, and NF-kb, while a positive correlation with miR-125a-5p in ITP patients. Patients who responded to steroids had significantly higher miR-125a-5p (P = 0.016) and significantly lower lncRNA-MEG3 (P < 0.001), CXCL13 (P = 0.005), and NF-kb (p = 0.002). Based on the ROC curves, lncRNA-MEG3 displayed the highest area under the curve (AUC) in the identification of organ bleeding (AUC = 0.805), the response to steroids (AUC = 0.853), and the need for splenectomy (AUC = 0.75).

Transcriptional upregulation of CXCL13 is correlated with a favorable response to immune checkpoint inhibitors in lung adenocarcinoma.

BACKGROUND: The chemokine CXCL13 is known to influence local anti-tumor immunity by recruiting immune cells and forming tertiary lymphoid structures (TLS). It has been hypothesized that TLS, led by the expression of CXCL13, could be a predictive or prognostic biomarker for immunotherapy. We investigated the predictive value of CXCL13 to immune checkpoint inhibitors (ICI) in lung adenocarcinoma. METHODS: We constructed an exploratory dataset (n = 63) and a validation dataset (n = 57) in metastatic lung adenocarcinoma patients treated with ICI. Based on the clinical response, the difference in gene expression profile, including CXCL13, was evaluated. RESULTS: From the exploratory dataset, CXCL13 expression was significantly upregulated in the ICI responders (p = 0.002). Survival analysis using a cut-off value of the median expression value of CXCL13 showed prolonged progression-free survival (PFS) (p = 0.004) and overall survival (OS) (p = 0.007). CXCL13 expression was correlated with other immune response genes, such as GZMA, CD8A, IFNG, PRF1, TLS-related gene sets and its receptor, CXCR5. Notably, subgroup analyses based on CXCL13 expression and CD8A showed that CXCL13-upregulated patients demonstrated comparably prolonged survival regardless of CD8A expression. In the validation dataset, CXCL13 upregulation also demonstrated a significant prolongation of both PFS (p = 0.050) and OS (p = 0.026). CONCLUSION: We observed that CXCL13 upregulation is correlated to better ICI response in lung adenocarcinoma. Our results support that CXCL13 could be an important chemokine in shaping the immunoactive tumor microenvironment which affects the anti-tumor effect of ICI.

CXCL13-CXCR5 axis: Regulation in inflammatory diseases and cancer.

Chemokine C-X-C motif ligand 13 (CXCL13), originally identified as a B-cell chemokine, plays an important role in the immune system. The interaction between CXCL13 and its receptor, the G-protein coupled receptor (GPCR) CXCR5, builds a signaling network that regulates not only normal organisms but also the development of many diseases. However, the precise action mechanism remains unclear. In this review, we discussed the functional mechanisms of the CXCL13-CXCR5 axis under normal conditions, with special focus on its association with diseases. For certain refractory diseases, we emphasize the diagnostic and therapeutic role of CXCL13-CXCR5 axis.

Identification of PSMB9 and CXCL13 as Immune-related Diagnostic Markers for Rheumatoid Arthritis by Machine Learning.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes significant physical and psychological damage. Although researchers have gained a better understanding of the mechanisms of RA, there are still difficulties in diagnosing and treating RA. We applied a data mining approach based on machine learning algorithms to explore new RA biomarkers and local immune cell status. METHODS: We extracted six RA synovial microarray datasets from the GEO database and used bioinformatics to obtain differentially expressed genes (DEGs) and associated functional enrichment pathways. In addition, we identified potential RA diagnostic markers by machine learning strategies and validated their diagnostic ability for early RA and established RA, respectively. Next, CIBERSORT and ssGSEA analyses explored alterations in synovium-infiltrating immune cell subpopulations and immune cell functions in the RA synovium. Moreover, we examined the correlation between biomarkers and immune cells to understand their immune-related molecular mechanisms in the pathogenesis of RA. RESULTS: We obtained 373 DEGs (232 upregulated and 141 downregulated genes) between RA and healthy controls. Enrichment analysis revealed a robust correlation between RA and immune response. Comprehensive analysis indicated PSMB9, CXCL13, and LRRC15 were possible potential markers. PSMB9 (AUC: 0.908, 95% CI: 0.853-0.954) and CXCL13 (AUC: 0.890, 95% CI: 0.836-0.937) also showed great diagnostic ability in validation dataset. Infiltrations of 16 kinds of the immune cell were changed, with macrophages being the predominant infiltrating cell type. Most proinflammatory pathways in immune cell function were activated in RA. The correlation analysis found the strongest positive correlation between CXCL13 and plasma cells, PSMB9, and macrophage M1. CONCLUSION: There is a robust correlation between RA and local immune response. The immune-related CXCL13 and PSMB9 were identified as potential diagnostic markers for RA based on a machine learning approach. Further in-depth exploration of the target genes and associated immune cells can deepen the understanding of RA pathophysiological processes and provide new insights into diagnosing and treating RA.

Activation of CXCL13/CXCR5 axis aggravates experimental autoimmune cystitis and interstitial cystitis/bladder pain syndrome.

The abnormal CXCL13/CXCR5 axis is involved in many inflammatory diseases and its selective inhibitor, TAK-799 has exhibited strong anti-inflammatory potency. The sequencing of clinical specimens from interstitial cystitis/bladder pain syndrome (IC/BPS) has shown that CXCL13 and CXCR5 are highly expressed, but the role of CXCL13/CXCR5 axis in IC/BPS has not been rarely reported. Therefore, in this study, we analyzed the GSE11783 sequencing data of IC/BPS patients and investigate the role and mechanism of CXCL13/CXCR5 axis and TAK-779 in the mouse model of experimental autoimmune cystitis (EAC). We verified that CXCL13 and CXCR5 were significantly up-regulated in EAC model. EAC mice exhibited increased bladder inflammatory factors (IL-6, TNF-α, IL-1ß), apoptosis-related proteins (Bax, Caspase-3, Caspase-8), frequency of voiding. Using TAK779 to block CXCL13/CXCR5 axis significantly attenuated these inflammatory damages and efficiently improved bladder function (significant reduction in micturition frequency, significant prolongation of inter-contraction interval). Further investigation showed that inhibiton of JNK and NF-kappaB activation, the bioinformatics analysis-indicated downstream signaling of CXCL13/CXCR5 axis, is responsible for the protective effect of TAK779. Taken together, we demonstrate that activation of the CXCL13/CXCR5 axis is involved in the pathophysiology of IC/BPS and EAC. Blocking CXCL13/CXCR5 axis activation by TAK-779 reduces bladder inflammation and improves bladder function in EAC mice.

Nano-trapping CXCL13 reduces regulatory B cells in tumor microenvironment and inhibits tumor growth.

Interactions between different cell types in the tumor microenvironment (TME) affect tumor growth. Tumor-associated fibroblasts produce C-X-C motif chemokine ligand 13 (CXCL13) which recruits B cells to the TME. B-cells in the TME differentiate into regulatory B cells (Bregs) (IL-10+CD1d+CD5+CD138+CD19+). We highlight these Breg cells as a new important factor in the modulation of the immunosuppressive TME in different desmoplastic murine tumor models. In addition, CXCL13 also stimulates epithelial-mesenchymal transition (EMT) of the tumor cells. The tumorigenic roles of CXCL13 led us to explore an innovative anti-cancer strategy based on delivering plasmid DNA encoding a CXCL13 trap to reduce Bregs differentiation and normalize EMT, thereby suppressing tumor growth. CXCL13 trap suppressed tumor growth in pancreatic cancer, BRAF-mutant melanoma, and triple-negative breast cancer. In this study, following treatment, the affected tumor remained dormant resulting in prolonged progression-free survival of the host.

Changes in the Expression and Functional Activities of C-X-C Motif Chemokine Ligand 13 (CXCL13) in Hyperplastic Prostate.

BACKGROUND: C-X-C motif chemokine ligand 13 (CXCL13), a member of the CXC subtype in chemokine superfamily, affects numerous biological processes of various types of cells and the progress of a great number of clinical diseases. The purpose of the current study was to reveal the internal mechanism between CXCL13 and benign prostatic hyperplasia (BPH). METHODS: Human serum, prostate tissues and human prostate cell lines (BPH-1, WPMY-1) were utilized. The effect of recombinant human CXCL13 (rHuCXCL13) protein and the influences of the knockdown/overexpression of CXCL13 on two cell lines were studied. Rescue experiments by anti-CXCR5 were also conducted. In vivo, rHuCXCL13 was injected into the ventral prostate of rats. Additionally, a tissue microarray of hyperplastic prostate tissues was constructed to analyze the correlations between CXCL13 and clinical parameters. RESULTS: CXCL13 was highly expressed in the prostate tissues and upregulated in the BPH group. It was observed that CXCL13 modulated cell proliferation, apoptosis, and the epithelial-mesenchymal transition (EMT) through CXCR5 via AKT and the ERK1/2 pathway in BPH-1, while it contributed to inflammation and fibrosis through CXCR5 via the STAT3 pathway in WPMY-1. In vivo, rHuCXCL13 induced the development of rat BPH. Additionally, CXCL13 was positively correlated with the prostate volume and total prostate specific antigen. CONCLUSIONS: Our novel data demonstrated that CXCL13 modulated cell proliferation, cell cycle, the EMT of epithelial cells, and induced the fibrosis of prostatic stromal cells via a variety of inflammatory factors, suggesting that CXCL13 might be rediscovered as a potential therapeutic target for the treatment of BPH.

ETV4 promotes pancreatic ductal adenocarcinoma metastasis through activation of the CXCL13/CXCR5 signaling axis.

Pancreatic ductal adenocarcinoma (PDAC) has the highest fatality rate of any solid tumor, with a five-year survival rate of only 10% in the USA. PDAC is characterized by early metastasis. More than 50% of patients present with distant metastases at the time of diagnosis, and the majority of patients will develop metastasis within 4 years after tumor resection. Despite extensive studies, the molecular mechanisms underlying PDAC metastasis remain unclear. The polyoma enhancer activator protein (PEA3) subfamily was reported to play a vital role in the initiation and progression of multiple tumors. Herein, we found that ETS variant 4 (ETV4) was highly expressed in PDAC tissues and associated with poor survival. Univariate and multivariate analyses revealed that ETV4 expression was an independent prognostic factor for patient survival. Further experiments showed that ETV4 overexpression promoted PDAC invasion and metastasis both in vitro and in vivo. For the first time, we demonstrated that, mechanistically, ETV4 increased CXCR5 expression by directly binding to the CXCR5 promoter region. Knockdown of CXCR5 significantly reversed ETV4-mediated PDAC migration and invasion, while CXCR5 overexpression exerted the opposite effects. Intriguingly, we found that CXCL13, a specific ligand of CXCR5, increased ETV4 expression and promoted PDAC invasion and metastasis by activating the ERK1/2 pathway. ETV4 knockdown significantly abrogated the enhanced migratory and invasive abilities induced by the CXCL13/CXCR5 axis. In addition, a CXCR5 neutralizing antibody disrupted the CXCL13/ETV4/CXCR5 positive feedback loop and inhibited cell migration and invasion. Overall, in this study, we demonstrated that ETV4 plays a vital role in PDAC metastasis and defined a novel CXCL13/ETV4/CXCR5 positive feedback loop. Targeting this pathway has implications for potential therapeutic strategies for PDAC treatment.

ZNF382 controls mouse neuropathic pain via silencer-based epigenetic inhibition of Cxcl13 in DRG neurons.

Nerve injury-induced changes of gene expression in dorsal root ganglion (DRG) are critical for neuropathic pain genesis. However, how these changes occur remains elusive. Here we report the down-regulation of zinc finger protein 382 (ZNF382) in injured DRG neurons after nerve injury. Rescuing this down-regulation attenuates nociceptive hypersensitivity. Conversely, mimicking this down-regulation produces neuropathic pain symptoms, which are alleviated by C-X-C motif chemokine 13 (CXCL13) knockdown or its receptor CXCR5 knockout. Mechanistically, an identified cis-acting silencer at distal upstream of the Cxcl13 promoter suppresses Cxcl13 transcription via binding to ZNF382. Blocking this binding or genetically deleting this silencer abolishes the ZNF382 suppression on Cxcl13 transcription and impairs ZNF382-induced antinociception. Moreover, ZNF382 down-regulation disrupts the repressive epigenetic complex containing histone deacetylase 1 and SET domain bifurcated 1 at the silencer-promoter loop, resulting in Cxcl13 transcriptional activation. Thus, ZNF382 down-regulation is required for neuropathic pain likely through silencer-based epigenetic disinhibition of CXCL13, a key neuropathic pain player, in DRG neurons.

Bioinformatics-based study to identify immune infiltration and inflammatory-related hub genes as biomarkers for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose principal pathological change is aggressive chronic synovial inflammation; however, the specific etiology and pathogenesis have not been fully elucidated. We downloaded the synovial tissue gene expression profiles of four human knees from the Gene Expression Omnibus database, analyzed the differentially expressed genes in the normal and RA groups, and assessed their enrichment in functions and pathways using bioinformatics methods and the STRING online database to establish protein-protein interaction networks. Cytoscape software was used to obtain 10 hub genes; receiver operating characteristic (ROC) curves were calculated for each hub gene and differential expression analysis of the two groups of hub genes. The CIBERSORT algorithm was used to impute immune infiltration. We identified the signaling pathways that play important roles in RA and 10 hub genes: Ccr1, Ccr2, Ccr5, Ccr7, Cxcl5, Cxcl6, Cxcl13, Ccl13, Adcy2, and Pnoc. The diagnostic value of these 10 hub genes for RA was confirmed using ROC curves and expression analysis. Adcy2, Cxcl13, and Ccr5 are strongly associated with RA development. The study also revealed that the differential infiltration profile of different inflammatory immune cells in the synovial tissue of RA is an extremely critical factor in RA progression. This study may contribute to the understanding of signaling pathways and biological processes associated with RA and the role of inflammatory immune infiltration in the pathogenesis of RA. In addition, this study shows that Adcy2, Cxcl13, and Ccr5 have the potential to be biomarkers for RA treatment.

The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13.

B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL-initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL-initiating cells prolonged murine survival, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.

CXC chemokine ligand-13 promotes metastasis via CXCR5-dependent signaling pathway in non-small cell lung cancer.

The CXC chemokine ligand-13 (CXCL13) is a chemoattractant of B cells and has been implicated in the progression of many cancers. So far, CXCL13 and its related receptor CXCR5 have been proved to regulate cancer cell migration as well as tumour metastasis. However, the role of CXCL13-CXCR5 axis in metastasis of lung cancer is still poorly understood. In this study, we found that CXCL13 and CXCR5 were commonly up-regulated in lung cancer specimens compared with normal tissues among different cohorts. Our evidence showed that CXCL13 obviously promoted migration of lung cancer cells, and this effect was mediated by vascular cell adhesion molecule-1 (VCAM-1) expression. We also confirmed that CXCR5, the major receptor responsible for CXCL13 function, was required for CXCL13-promoted cell migration. We also test the candidate components which are activated after CXCL13 treatment and found that phospholipase C-ß (PLCß), protein kinase C-α (PKCα) and c-Src signalling pathways were involved in CXCL13-promoted cell migration and VCAM-1 expression in lung cancer cells. Finally, CXCL13 stimulated NF-κB transcription factor in lung cancer cells, contributing to VCAM-1 expression in translational level. These evidences propose a novel insight into lung cancer metastasis which is regulated by CXCL13.

The cytokines HGF and CXCL13 predict the severity and the mortality in COVID-19 patients.

The objective of the present study was to identify biological signatures of severe coronavirus disease 2019 (COVID-19) predictive of admission in the intensive care unit (ICU). Over 170 immunological markers were investigated in a 'discovery' cohort (n = 98 patients) of the Lausanne University Hospital (LUH-1). Here we report that 13 out of 49 cytokines were significantly associated with ICU admission in the three cohorts (P < 0.05 to P < 0.001), while cellular immunological markers lacked power in discriminating between ICU and non-ICU patients. The cytokine results were confirmed in two 'validation' cohorts, i.e. the French COVID-19 Study (FCS; n = 62) and a second LUH-2 cohort (n = 47). The combination of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 13 (CXCL13) was the best predictor of ICU admission (positive and negative predictive values ranging from 81.8% to 93.1% and 85.2% to 94.4% in the 3 cohorts) and occurrence of death during patient follow-up (8.8 fold higher likelihood of death when both cytokines were increased). Of note, HGF is a pleiotropic cytokine with anti-inflammatory properties playing a fundamental role in lung tissue repair, and CXCL13, a pro-inflammatory chemokine associated with pulmonary fibrosis and regulating the maturation of B cell response. Up-regulation of HGF reflects the most powerful counter-regulatory mechanism of the host immune response to antagonize the pro-inflammatory cytokines including CXCL13 and to prevent lung fibrosis in COVID-19 patients.