Pro-tumor Tfh2 cells induce detrimental IgG4 production and PGE2-dependent IgE inhibition in pancreatic cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1015278 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26033900.fastq.gz | Fastqsanger.gz | |||
| SRR26034900.fastq.gz | Fastqsanger.gz | |||
| SRR26033901.fastq.gz | Fastqsanger.gz | |||
| SRR26034901.fastq.gz | Fastqsanger.gz | |||
| SRR26033902.fastq.gz | Fastqsanger.gz |
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Project description:Pro-tumor Tfh2 cells induce detrimental IgG4 production and PGE2-dependent IgE inhibition in pancreatic cancer (tfh)
| PRJNA1015281 | ENA
Project description:Pro-tumor Tfh2 cells induce detrimental IgG4 production and PGE2-dependent IgE inhibition in pancreatic cancer (tumor)
| PRJNA1015280 | ENA
Project description:Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells are relevant immunoregulators in cancer, and often correlate with better survival. How the Th2-skewed microenvironment in PDAC modulates the differentiation of Tfh cells and their immunoregulatory function is unknown. Methods: We carried out high-dimensional flow cytometry and T-cell receptor- and RNA-sequencing, as well as bioinformatics, immunohistochemistry and in vitro mechanistic studies. Findings: We identified Tfh1-, Tfh2-, and Tfh17-like cell clusters in the blood, tumors and tumor draining lymph-nodes (TDLNs) of chemo-naïve PDAC patients and showed that high percentages of Tfh2 cells within the tumor tissue and TDLNs correlated with reduced patient survival. Moreover, only Tfh2 cells were highly activated and were reduced in frequency in patients who responded to neoadjuvant chemotherapy. RNA-sequencing analysis of immunoglobulin expression showed that tumor and TDLN samples expressed all immunoglobulin (IGH) isotypes apart from IGHE. Consistent with these findings, Tfh2 cells differentiated in vitro by tumor microenvironment-conditioned dendritic cells promoted the production of anti-inflammatory IgG4 antibodies by co-cultured B cells, dependent on IL-13. Moreover, unexpectedly, Tfh2 cells inhibited the secretion of pro-inflammatory IgE, dependent on prostaglandin E2. Interpretation: Our results indicate that in PDAC, highly activated pro-tumor Tfh2 favor anti-inflammatory IgG4 production, while inhibit pro-inflammatory IgE. Thus, targeting the circuits that drive Tfh2 cells, in combination with chemotherapy, may re-establish beneficial anti-tumor Tfh–B cell interactions and facilitate more effective treatment.
2023-10-04 | GSE242915 | GEO
Project description:Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells are relevant immunoregulators in cancer, and often correlate with better survival. How the Th2-skewed microenvironment in PDAC modulates the differentiation of Tfh cells and their immunoregulatory function is unknown. Methods: We carried out high-dimensional flow cytometry and T-cell receptor- and RNA-sequencing, as well as bioinformatics, immunohistochemistry and in vitro mechanistic studies. Findings: We identified Tfh1-, Tfh2-, and Tfh17-like cell clusters in the blood, tumors and tumor draining lymph-nodes (TDLNs) of chemo-naïve PDAC patients and showed that high percentages of Tfh2 cells within the tumor tissue and TDLNs correlated with reduced patient survival. Moreover, only Tfh2 cells were highly activated and were reduced in frequency in patients who responded to neoadjuvant chemotherapy. RNA-sequencing analysis of immunoglobulin expression showed that tumor and TDLN samples expressed all immunoglobulin (IGH) isotypes apart from IGHE. Consistent with these findings, Tfh2 cells differentiated in vitro by tumor microenvironment-conditioned dendritic cells promoted the production of anti-inflammatory IgG4 antibodies by co-cultured B cells, dependent on IL-13. Moreover, unexpectedly, Tfh2 cells inhibited the secretion of pro-inflammatory IgE, dependent on prostaglandin E2. Interpretation: Our results indicate that in PDAC, highly activated pro-tumor Tfh2 favor anti-inflammatory IgG4 production, while inhibit pro-inflammatory IgE. Thus, targeting the circuits that drive Tfh2 cells, in combination with chemotherapy, may re-establish beneficial anti-tumor Tfh–B cell interactions and facilitate more effective treatment.
2023-10-04 | GSE242916 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-10-04 | GSE242917 | GEO
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells are relevant immunoregulators in cancer, and often correlate with better survival. How the Th2-skewed microenvironment in PDAC modulates the differentiation of Tfh cells and their immunoregulatory function is unknown.MethodsWe carried out high-dimensional flow cytometry and T-cell receptor- and RNA-sequencing, as well as bioinformatics, immunohistochemistry and in vitro mechanistic studies.FindingsWe identified Tfh1-, Tfh2-, and Tfh17-like cell clusters in the blood, tumors and tumor-draining lymph-nodes (TDLNs) of chemo-naïve PDAC patients and showed that high percentages of Tfh2 cells within the tumor tissue and TDLNs correlated with reduced patient survival. Moreover, only Tfh2 cells were highly activated and were reduced in frequency in patients who responded to neoadjuvant chemotherapy. RNA-sequencing analysis of immunoglobulin expression showed that tumor and TDLN samples expressed all immunoglobulin (IGH) isotypes apart from IGHE. Consistent with these findings, Tfh2 cells differentiated in vitro by tumor microenvironment-conditioned dendritic cells promoted the production of anti-inflammatory IgG4 antibodies by co-cultured B cells, dependent on IL-13. Moreover, unexpectedly, Tfh2 cells inhibited the secretion of pro-inflammatory IgE, dependent on prostaglandin E2.InterpretationOur results indicate that in PDAC, highly activated pro-tumor Tfh2 favor anti-inflammatory IgG4 production, while inhibit pro-inflammatory IgE. Thus, targeting the circuits that drive Tfh2 cells, in combination with chemotherapy, may re-establish beneficial anti-tumor Tfh-B cell interactions and facilitate more effective treatment.FundingResearch grants from the Italian Association for Cancer Research (AIRC) IG-19119 to MPP and the AIRC Special Program in Metastatic disease: the key unmet need in oncology, 5 per Mille no. 22737 to CB, MF, CD, MR and MPP; the ERA-NET EuroNanoMed III (a collaborative european grant financed by the Italian Ministry of Health, Italy) project PANIPAC (JTC2018/041) to MPP; the Fondazione Valsecchi to SC.
| S-EPMC10542011 | biostudies-literature
Project description:Prostaglandin E2 (PGE2) is overexpressed in many tumors and plays an important role in suppressing T-cell function. In this study, we investigated the effect of PGE2 in human T-cells. Importantly, PGE2 caused profound transcriptomic changes both in unstimulated and exhausted T-cells with many genes and pathways altered including T-cell lipid metabolism. Our study suggests that PGE2-induced metabolic reprogramming is detrimental to dysfunctional T-cells and TIL, and its manipulation could be used to dampen the immunosuppressive effects of PGE2.
2024-03-08 | GSE227316 | GEO
Project description:Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4-restricted plasma cells in a variety of organs. Clinical presentation is heterogeneous and pathophysiological mechanisms of IgG4-related autoimmunity remain elusive. Secondary parenchymal lesions of IgG4-RD in the central nervous system (CNS) are rare and there are very few cases of IgG4-RD with isolated CNS manifestation. Patients suffering from IgG4-RD frequently require prolonged treatment with glucocorticoids and are often unable to taper these medications. By leveraging single-cell sequencing of the cerebrospinal fluid (CSF) of a patient with an unusual inflammatory intracranial pseudotumor we provide novel insights into the immuno-pathophysiology of IgG4-RD by illustrating an IgG4-RD-associated polyclonal T cell response in the CSF and multifaceted cell-cell interaction between immune cell subsets and pathogenic B cells.
2021-06-19 | E-MTAB-10479 | biostudies-arrayexpress
Project description:Transcriptome analysis in patients with IgG4-RD and healthy controls IgG4-related disease (IgG4-RD) is a new emerging disease entity characterized by elevated serum IgG4 concentrations and tissue tumefaction or infiltration by IgG4-positive plasma cells. At present, however, it is not clear whether IgG4-RD is caused by abnormalities in acquired immunity, like autoimmune diseases, or whether the excess production of IgG4 is a true cause of IgG4-RD or an epiphenomenon associated with inflammatory and/or allergic reactions. We therefore attempted to identify genes related to the pathogenesis or clinicopathology of IgG4-RD. Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IgG4-RD before and after steroid therapy and from healthy controls. Total RNA was extracted and DNA microarray analysis was performed to screen for genes showing changes in expression. To exclude any gender-related differences in gene expression, DNA microarray analysis was performed only on samples obtained from male patients and controls. Total RNA was reverse transcribed to cDNA using AmbionM-BM-. WT Expression kits (Applied Biosystems, Foster City, CA), labeled with GeneChipM-BM-. WT Terminal Labeling and Controls kits (Affymetrix, Santa Clara, CA), and hybridized to GeneChipM-BM-. Human Gene 1.0 ST Arrays (Affymetrix), which include 28869 probes. Digitalized image data were processed using GeneChipM-BM-. Operating Software (Affymetrix).
2015-03-03 | E-GEOD-66465 | biostudies-arrayexpress
Project description:The molecular pathogenesis of orbital lymphoproliferative disorders, such as immunoglobulin G4-related ophthalmic disease (IgG4-ROD) and orbital mucosa-associated lymphoid tissue (MALT) lymphoma, remains essentially unknown. Differentiation between the two disorders, which is important since work-up and treatment can vary greatly, is often challenging due to the lack of specific biomarkers. Although miRNAs play an important role in the regulation of carcinogenesis and inflammation, the relationship between miRNA and orbital lymphoproliferative diseases remains unknown. A comprehensive analysis of 2,565 miRNAs was performed in biopsied specimens and serum of 17 cases with IgG4-ROD and 21 cases with orbital MALT lymphoma. We identified specific miRNA signatures, their miRNA target pathways, and network analysis associated with IgG4-ROD and orbital MALT lymphoma. Machine-learning analysis identified miR-202-3p and miR-7112-3p as the best discriminators of IgG4-ROD and orbital MALT lymphoma, respectively. In the tissue pathway, Longevity regulating pathway in IgG4-ROD and MAPK signaling pathway in orbital MALT lymphoma were most enriched by downregulated miRNAs. This is the first evidence of the miRNA profile in biopsied specimens and serum of patients with IgG4-ROD and orbital MALT lymphoma. These data will be useful for developing diagnostic and therapeutic interventions, as well as elucidating of these disorders.
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