γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1033651 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26588459.fastq.gz | Fastqsanger.gz | |||
| SRR26588460.fastq.gz | Fastqsanger.gz | |||
| SRR26588461.fastq.gz | Fastqsanger.gz | |||
| SRR26588462.fastq.gz | Fastqsanger.gz | |||
| SRR26588463.fastq.gz | Fastqsanger.gz |
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Project description:Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αβ T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids.
2023-11-09 | GSE246571 | GEO
Project description:Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αβ T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential γδ T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for γδ T cell activation, as well as differential expression of PDL1/CD274 in cancer, E6/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of γδ T cells with cervical cancer organoids, providing a novel in vitro model to optimize innovative patient-specific immunotherapies for cervical cancer.
| S-EPMC10711208 | biostudies-literature
Project description:Cervical cancer is a common gynecological malignancy, often caused by high-risk human papillomavirus. There is a paucity of human-derived culture systems to study cervical epithelium and the cancers derived thereof. Here, we describe a long-term culturing protocol for ecto- and endocervical epithelia, which generates 3D organoids that stably recapitulate the two tissues of origin. In the example of successful HSV-1 infection, we show that the organoid-based cervical models serve as promising platforms for studying sexually transmitted pathogens. Starting from Pap-brush material, a small biobank of patient-derived tumoroids was established that retained the causative HPV genomes. One of these uniquely carried the poorly characterized HPV30 subtype, implying a potential role in carcinogenesis. The tumoroids displayed differential responses to common chemotherapeutics and grew as xenografts in mice. This study describes an experimental platform for cervical (cancer) research and for future personalized medicine approaches. Purpose: Transcriptome analysis was performed on organoids/tissues derived from human ecto- and endocervix as well as associated malignancies to characterize the new organoid-based platform. Methods: Ectocervical organoids and tumoroid lines were cultured in M7 media, whereas endocervical organoids in M7+4 media prior harvesting for RNA extraction (see paper for details). Additionally, RNA was extracted from healthy ecto-and endocervical tissue biopsies as well as from primary cells collected via Pap brush method from cervical cancer patients. The libraries were prepared by the Utrecht Sequencing Facility (USEQ) based on polyA enrichment. Sequencing was performed on an Illumina NextSeq500 by using 75-bp single-end or paired-end sequencing. Reads were aligned to the human reference genome (GRCh37) using Burrows-Wheeler Aligner (BWA) (v0.5.9). Viral sequences of different HPV subtypes were detected in the RNA-seq data of the different tumoroid lines and tissues by using VirusSeq-CLI, a wrapper around the VirusSeq pipeline. Results: Ectocervical and endocervical organoids display distinct transcriptomic profiles that can be maintained in cultures for long term. Similarily, the the gene expression profile of tumor organoids clusters apart from healthy counterparts and shows evident tumor-like characteristics. Tumor organoids show expression of causative HPV oncogenes.
2021-03-05 | GSE168244 | GEO
Project description:The mammalian gastrointestinal tract harbors thousands of bacterial species that include symbionts as well as potential pathogens. The immune responses that limit access of these bacteria to underlying tissue remain poorly defined. In this study, we used microarrays to uncover the transcriptional responses that occur in small intestinal γδ intraepithelial lymphocytes following bacterial challenge. γδ intraepithelial lymphocytes (γδ IEL) were isolated by flow cytometry from the small intestines of germ-free mice, or from age- and sex-matched conventionally-raised counterparts. We extracted RNAs from these purified γδ IEL for analysis on Affymetrix DNA microarrays. The mice were all >8 weeks in age, and each sample represents a pool of RNAs from 5-8 mice.
2011-04-06 | E-GEOD-28437 | biostudies-arrayexpress
Project description:Abstract: Bovine tuberculosis (bTB), caused by infection with Mycobacterium bovis, continues to cause significant issues for the global agriculture industry as well as for human health. An incomplete understanding of the host immune response contributes to the challenges of control and eradication of this zoonotic disease. In this study, high-throughput bulk RNA sequencing (RNA-seq) was used to characterize differential gene expression in γδ T cells – a subgroup of T cells which bridge innate and adaptive immunity and have specific anti-mycobacterial response mechanisms. γδ T cell subsets are classified on the basis of expression of a pathogen-recognition receptor known as Workshop Cluster 1 (WC1) and we hypothesised that bTB infection may alter the phenotype and function of specific γδ T cell subsets. Peripheral blood was collected from naturally M. bovis-infected (positive for single intradermal comparative tuberculin test (SICTT) and IFN-γ ELISA) and age- and sex-matched, non-infected control Holstein-Friesian cattle. γδ T subsets were isolated using fluorescence activated cell sorting (n = 10-12 per group) and high-quality RNA extracted from each purified lymphocyte subset (WC1.1+, WC1.2+, WC1- and γδ-) was used to generate transcriptomes using bulk RNA-seq (n = 6 per group, representing a total of 48 RNA-seq libraries). Relatively low numbers of differentially expressed genes (DEGs) were observed between most cell subsets; however, 163 genes were significantly differentially expressed in the M. bovis-infected compared to control groups for the WC1.1+ γδ T cell compartment (Log 2 FC ≥ 1.5 and FDR P adj ≤ 0.1). The majority of these DEGs (146) were significantly increased in expression in cells from the bTB+ cattle and included genes encoding transcription factor (TBX21 and EOMES), chemokine receptors (CCR5 and CCR7), granzymes (GZMA, GZMM and GZMH) and multiple killer cell immunoglobulin-like receptors (KIR) indicating cytotoxic functions. Biological pathway overrepresentation analysis revealed enrichment of genes with multiple immune functions including cell activation, proliferation, chemotaxis and cytotoxicity of lymphocytes. In conclusion, WC1.1+ γδ T cells have been proposed as major regulatory cell subset in cattle, and we provide evidence for preferential differential activation of this specific subset in cattle naturally infected with M. bovis. Understanding the role of these critical immune cells during mycobacterial infection contributes to our understanding of host immunity to bTB and identifies multiple novel cytotoxic functions of WC1.1+ γδ T cells.
2023-07-01 | E-MTAB-13111 | biostudies-arrayexpress
Project description:Transcriptome Profiling of Tumor-Infiltrating Lymphocyte-Mediated Cytotoxicity against Patient-Derived Lung Cancer Organoids
| PRJEB101066 | ENA
Project description:Transcriptome Profiling of Tumor-Infiltrating Lymphocyte-Mediated Cytotoxicity against Patient-Derived Lung Cancer Organoids
| PRJEB101073 | ENA
Project description:Transcriptome Profiling of Tumor-Infiltrating Lymphocyte-Mediated Cytotoxicity against Patient-Derived Lung Cancer Organoids
| PRJEB101854 | ENA
Project description:RNA expression of unstimulated γδ-T cells,γδ-TCR-stimulated γδ-T cells, unstimulated αβ-TCR transduced γδ-T cells and αβ-TCR-stimulated αβ-TCR transduced γδ-T cells.
2023-09-07 | GSE216880 | GEO
Project description:The anatomic location and immunologic characteristics of brain tumors result in strong lymphocyte suppression. Consequently, conventional immunotherapies targeting CD8 T-cells are ineffective against brain tumors. Tumor cells escape immunosurveillance by various mechanisms, and tumor cell metabolism can affect the metabolic states and functions of tumor-infiltrating lymphocytes. Oxygen tension is one important factor influencing immune responses. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected γδ T-cell-mediated antitumor immune responses but not those of conventional T-cells. Specifically, tumor hypoxia activated the γδ T-cell protein kinase A (PKA) pathway at a transcriptional level, resulting in repression of NKG2D expression. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of γδ T-cells. These results reveal a hypoxia-mediated mechanism by which brain tumors and γδ T-cells interact and emphasize the importance of γδ T-cells for antitumor immunity against brain tumors.
2020-12-04 | GSE159542 | GEO