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Concurrent chemoradiotherapy (CCRT) is the standard treatment for advanced cervical cancer, but tumor recurrence within 3–5 years remains a significant challenge. In this study, using 10 × single-cell sequencing, we constructed a cellular atlas of the tumor microenvironment from six CSCC patients, including three with recurrence and three without, prior to CCRT. We analyzed cellular subsets, focusing on T cells, myeloid cells and cancer associated fibroblasts (CAFs), and their interactions within the tumor. Key findings revealed that CXCL13 + T cell subsets were significantly increased in non-recurrent tumors and acted as major signal senders. In recurrent tumors, FOXP3 + and IL2RA + Tregs were the primary mediators of cell communications. CXCL13 + CD8 + T cells interacted with SPP1 + tumor-associated macrophages (TAMs) in non-recurrent tumors, while in recurrent tumors, they interacted with CD163 + TAMs. Moreover, in recurrent tumor tissues, this subset demonstrates a preferential interaction with MMP3 + CAFs. The study also identified five genes (PDCD1, CXCL13, TOX, RGS1, and ALOX5AP) based on CXCL13 + T cell signature to construct predictive models for recurrence, with the random forest model showing the best performance. This study provides new insights into recurrence mechanisms in CSCC and suggests that increasing CXCL13 + T cells could be a potential therapeutic strategy.

Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers 1 . Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota 2 , 3 . Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8 + T cells and CD20 + B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8 + CD20 + tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7 + naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy. The co-occurrence of tumour-associated CD8 + T cells and CD20 + B cells, and the formation of tertiary lymphoid structures, are linked with improved survival in cohorts of patients with metastatic melanoma.

Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4⁺ helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1⁺CXCL13⁺ T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46%of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5⁺ normal B cells in close proximity to CXCL13⁺ T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1⁺CXCL13⁺ T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL (P = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1⁺CXCL13⁺ T cells as a treatment target in LR-CHL.

To examine chemokine expression in children with Respiratory Syncytial Virus (RSV) bronchiolitis and evaluate its clinical utility for early warning and prognosis. Five hospitalised RSV bronchiolitis children and five matched controls were studied. To validate findings, 50 RSV infants and 30 controls were assessed for recurrent wheezing after 1 year. Blood leukocyte RNA-seq identified RSV-associated hub genes via GO/KEGG analysis, with flow cytometry confirming chemokine expression. Twelve hub genes were identified, with 712 differentially expressed genes (292 upregulated, 420 downregulated). RSV patients showed elevated CXCL2, CXCL12, CXCL13, CCL13, and CCL24 ( P  < 0.05). CXCL12 was higher in moderate-to-severe cases (Area Under the Curve, AUC = 0.835, 95% CI 0.714–0.956, P  < 0.05), while CXCL13 was elevated in recurrent wheezers (AUC = 0.851, 95% CI 0.711–0.991, P  < 0.05). CXCL12 predicted severity, and CXCL13 predicted recurrence (ROC-confirmed, P  < 0.05). CXCL12 and CXCL13 may serve as biomarkers for assessing RSV bronchiolitis severity and predicting recurrence, aiding early clinical evaluation and prognosis.

BackgroundChemokine (C-X-C motif) ligand 13 (CXCL13/BLC/BCA-1) is a cytokine from C-X-C chemokine family, which is selectively chemotactic for B cells. Previous research has demonstrated that high CXCL13 expression is correlated to poor prognosis in various cancers. However, the association between CXCL13 expression and gastric cancer is still unclear.MethodsIntratumoral CXCL13 expression was evaluated by immunohistochemistry using a semi-quantitative method (modified H-score) in a testing set of 214 and a validation set of 227 randomly selected gastric cancer patients resected in 2008 in one institution. The median value was used as the cut-off point. We performed correlative analysis of CXCL-13 expression with clinicopathological variables, Kaplan–Meier analysis for association with overall survival (OS), and multivariate modeling.ResultsHigh CXCL13 expression was associated with larger tumor diameter and shorter OS. By multivariate analysis, CXCL13 expression was associated with OS independently from clinicopathological factors. Within the T2–4 stage patients group, low CXCL13 expression was associated with longer survival, especially in the subgroup of patients (57.6%) who received adjuvant chemotherapy.ConclusionsIntratumoral CXCL13 expression appears as an independent prognostic marker for patients after gastric cancer resection. In addition, CXCL13 expression may serve as a predictive biomarker of response to postoperative adjuvant chemotherapy in these patients.

Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4+ T follicular helper (GC Tfh) cells problematic. The CXCL13–CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS⁺ (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.

Identifying predictive biomarkers for immune checkpoint inhibitor (ICI) treatment is critical for gastric cancer (GC) prognosis. C-X-C motif chemokine ligand 13(CXCL13) plays an important role in immune regulation by binding exclusively to its receptor CXCR5. However, its role, underlying mechanisms, and prognostic significance in ICI-treated GC patients remain controversial. This study investigated the clinical significance of CXCL13 and its potential immunomodulatory function in GC patients. A total of 144 GC patients from two cohorts, who received a combination of chemotherapy and anti-PD-1 antibody, were analyzed. The expression of CXCL13 was assessed using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay. Associations between CXCL13, CXCR5, CD8, and CD4 were assessed by IHC and immunofluorescence. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards model. The treatment response to CXCL13 and anti-PD-1 antibody was investigated using a subcutaneous xenograft tumor mouse model. The results suggested that patients with high CXCL13 expression had prolonged survival. High CXCL13 expression exhibited increased infiltration of CXCR5+CD8+ T cells and was associated with better outcomes. The combined assessment of CXCL13, CXCR5, and CD8+ T cells served as an independent predictor of prognosis. Additionally, CXCR5 and CD8+ T cells were enriched in tertiary lymphoid structures (TLSs), which conferred a prognostic benefit in the presence of high CXCL13 expression. CXCL13, in combination with anti-PD-1 therapy, retarded tumor growth in vivo, resulting in increased infiltration of CXCR5+CD8+ T cells. This study identified CXCL13 as a prognostic factor in GC patients receiving ICI therapy, emphasizing its critical role in the antitumor microenvironment via CXCR5+CD8+ T cells.

In human inflammatory sites, PD-1 hi CXCR5 − CD4 + T cells are involved in the formation of ectopic lymphoid-like structures (ELSs) by the secretion of chemokine CXCL13, but how the transcription of CXCL13 is regulated in CD4 + T cells is still unclear. Here we show that Sox4 is a key transcription factor for CXCL13 production in human CD4 + T cells under inflammatory conditions. In vitro TGF-β + , IL-2-neutralizing culture conditions give rise to PD-1 hi CXCR5 − CD4 + T cells that preferentially express CXCL13, and transcriptome analysis and lentiviral overexpression indicate Sox4 association with the CXCL13 transcription. In vivo, Sox4 is significantly upregulated in synovial CD4 + T cells, when compared with blood CD4 + T cells, from patients with rheumatoid arthritis (RA), and further correlates with ELS formation in RA synovium. Overall, our studies suggest that Sox4 contributes to CXCL13 production and ELS formation at inflammatory sites in humans. At inflammatory sites, ectopic lymphoid-like structures (ELS) can be induced through the function of chemokine CXCL13 produced by CD4 + T cells. Here the authors show that a transcription factor, Sox4, induces the expression of CXCL13 in CD4 T cells in vitro, and is associated with ELS formation in patients with rheumatoid arthritis.

Tertiary lymphoid structures are immune cell aggregates linked with cancer outcomes, but their interactions with tumour cell aggregates are unclear. Using nasopharyngeal carcinoma as a model, here we analyse single-cell transcriptomes of 343,829 cells from 77 biopsy and blood samples and spatially-resolved transcriptomes of 31,316 spots from 15 tumours to decipher their components and interactions with tumour cell aggregates. We identify essential cell populations in tertiary lymphoid structure, including CXCL13 + cancer-associated fibroblasts, stem-like CXCL13 + CD8 + T cells, and B and T follicular helper cells. Our study shows that germinal centre reaction matures plasma cells. These plasma cells intersperse with tumour cell aggregates, promoting apoptosis of EBV-related malignant cells and enhancing immunotherapy response. CXCL13 + cancer-associated fibroblasts promote B cell adhesion and antibody production, activating CXCL13 + CD8 + T cells that become exhausted in tumour cell aggregates. Tertiary lymphoid structure-related cell signatures correlate with prognosis and PD-1 blockade response, offering insights for therapeutic strategies in cancers. The interactions between tertiary lymphoid structures (TLS) and tumor cell aggregates remain to be investigated. Here, single-cell and spatial transcriptomics reveal the cellular composition, formation, and function of TLS during tumour progression and immunotherapy response in nasopharyngeal carcinoma.

Neuropathic pain is an unneglectable pain condition with limited treatment options owing to its enigmatic underlying mechanisms. Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) is involved in the progression of a spectrum of human cancers. However, its role in neuropathic pain remains undiscovered. In the present study, we established a mouse spinal nerve ligation (SNL) model, and a significant upregulation of SNHG5 was observed. Then we knocked down SNHG5 level in mouse L5 dorsal root ganglion (DRG) by delivering specific short hairpin RNA against SNHG5 with adenovirus vehicle. Mouse paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in response to mechanical stimuli was increased after SNHG5 knockdown, accompanied with decreased protein levels of glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule 1 (IBA-1). Besides, SNHG5 directly modulated the expression of miR-154-5p, which was downregulated in SNL mice. MiR-154-5p inhibition abolished the effect of SNHG5 knockdown on mouse behavioral tests and GFAP and IBA-1 levels. In addition, we validated that C-X-C motif chemokine 13 (CXCL13) was a novel downstream target of miR-154-5p, and CXCL13 level was positively related to that of SNHG5 in SNL mice. In conclusion, our study demonstrated that SNHG5 knockdown alleviated neuropathic pain and inhibited the activation of astrocytes and microglia by targeting the miR-154-5p/CXCL13 axis, which might be a novel therapeutic target for neuropathic treatment clinically.