Thematische Bibliographien / Tertiary lymphoid structure (TLS)

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Auswahl der wissenschaftlichen Literatur zum Thema „Tertiary lymphoid structure (TLS)“

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Veröffentlicht am 23. November 2024

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Zeitschriftenartikel zum Thema "Tertiary lymphoid structure (TLS)"

Gorecki, Grace, Lan Gardner Coffman, Sarah E. Taylor und Tullia C. Bruno. „Tertiary lymphoid structure prevalence and prognostic value in cervical cancer.“ Journal of Clinical Oncology 41, Nr. 16_suppl (01.06.2023): e17521-e17521. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e17521.

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e17521 Background: Recurrent or progressive cervical cancer have limited second-line treatment options. Response rates are often poor to second-line therapy (average response rate of 15%). Identification of factors which predict response to immunotherapy and targets to enhance the immune response are critically needed in cervical cancer. Chronic inflammation can initiate an immune response in non-secondary lymphoid organs (SLO) and form a Tertiary Lymphoid Structure (TLS). TLS is composed of immune cells clustered and organized and responsible for immune cell chemotaxis, which impacts cancer therapeutic response. Chemokine ligand 13 (CXCL13) is related to B cell attraction and TLS formation. Recent work from our group demonstrated human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) exhibited greater tumor infiltrating B cells (TIL-Bs) and TLS vs HPV negative disease indicating a role for viral infection in immune infiltration. Most cervical cancer is caused by HPV infection, therefore we investigated prognostic significance of immune infiltration in cervix cancer. Methods: A cohort analysis was conducted on 43 patients diagnosed with early stage cervical cancer. The presence of B cells, CD8 T cells, and CXCL13 was analyzed using singleplex immunohistochemistry staining. We separated infiltration into high infiltration and low infiltration, defined by their median value. TLS was identified using a multiplex immunofluorescence for TLS maturity panel. Histological findings were associated with cohort data. Results: High intratumoral infiltration of CD8 T cells was associated with longer overall survival in cancer patients. Median survival was 45 months for low infiltration group, whereas it was not reached by higher T cell infiltration (p < 0.05). The prognostic value of T cell infiltration was stronger in adenocarcinoma, typically associated with worse outcomes, than in squamous cell carcinoma. In adenocarcinoma, median survival was 58 months for low T cell infiltration, it was not reached by high infiltration group. CXCL13 levels were prognostic for recurrence-free survival, with median survival of 53 months in low expression group and not reached in high CXCL13 presence group (p < 0.05). The presence of TLS compared to low B cell infiltration was associated to higher survival, with 0% of deaths in the TLS group vs 40% in low B cell infiltration. While there was no correlation between TIL-B and patient outcomes, the presence of B cells in the aggregation process and higher CXCL13 levels were associated with improved survival, with 9% deaths vs 36% in low B cell group, possibly due to the support of TLS formation by B cell aggregation surrounded by CXCL13. Conclusions: Our study suggests that the presence of TLS, whether forming or established, is linked to improved clinical outcomes in cervical cancer. Further research is necessary to investigate the response of this cancer type to immunotherapy.

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Zou, Ji’an, Yingzhe Zhang, Yue Zeng, Yurong Peng, Junqi Liu, Chaoyue Xiao und Fang Wu. „Tertiary Lymphoid Structures: A Potential Biomarker for Anti-Cancer Therapy“. Cancers 14, Nr. 23 (02.12.2022): 5968. http://dx.doi.org/10.3390/cancers14235968.

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A tertiary lymphoid structure (TLS) is a special component in the immune microenvironment that is mainly composed of tumor-infiltrating lymphocytes (TILs), including T cells, B cells, DC cells, and high endothelial venules (HEVs). For cancer patients, evaluation of the immune microenvironment has a predictive effect on tumor biological behavior, treatment methods, and prognosis. As a result, TLSs have begun to attract the attention of researchers as a new potential biomarker. However, the composition and mechanisms of TLSs are still unclear, and clinical detection methods are still being explored. Although some meaningful results have been obtained in clinical trials, there is still a long way to go before such methods can be applied in clinical practice. However, we believe that with the continuous progress of basic research and clinical trials, TLS detection and related treatment can benefit more and more patients. In this review, we generalize the definition and composition of TLSs, summarize clinical trials involving TLSs according to treatment methods, and describe possible methods of inducing TLS formation.

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Lynch, Kevin T., Samuel J. Young, Max O. Meneveau, Nolan A. Wages, Victor H. Engelhard, Craig L. Slingluff Jr und Ileana S. Mauldin. „Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma“. Journal for ImmunoTherapy of Cancer 9, Nr. 6 (Juni 2021): e002273. http://dx.doi.org/10.1136/jitc-2020-002273.

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BackgroundTertiary lymphoid structures (TLSs) are immune aggregates in peripheral tissues that may support adaptive immune responses. Their presence has been associated with clinical response to checkpoint blockade therapy (CBT), but it is unknown whether TLS have prognostic significance independent of CBT in melanoma. We hypothesized that TLS in melanoma metastases would be associated with increased intratumoral lymphocyte infiltration, but that the intra-TLS immunological milieu would be distinct from the intratumoral immunological milieu. We also hypothesized that the presence of TLS would be associated with improved survival, and that TLS maturation or intra-TLS lymphocyte activity would also correlate with survival.MethodsCutaneous melanoma metastases (CMM) from 64 patients were evaluated by multiplex immunofluorescence for the presence and maturation status of TLS. Intra-TLS lymphocyte density, proliferation and B-cell Ig somatic hypermutation (AID+) were analyzed, as were markers of T-cell exhaustion and Th1/Tc1 differentiation. Associations between TLS maturation and intra-TLS immunologic activity were assessed, as well as associations with intratumoral immune cell infiltration. Independent associations with overall survival (OS) were assessed using log-rank tests and Cox proportional hazards models.ResultsTLS were identified in 30 (47%) of 64 CMM (TLS+) and were associated with increased intratumoral lymphocyte infiltration. However, proliferation of intra-TLS lymphocytes did not correlate with intratumoral lymphocyte proliferation. Most were early TLS; however, subsets of primary or secondary follicle-like TLS were also present. TLS+ lesions were associated with lower risk of tumor recurrence after metastasectomy and with improved OS in multivariate analyses (HR 0.51, p=0.04). OS was longer for TLS with low fractions of CD21+ B-cells (HR 0.29, p=0.02) and shorter for those with low AID+ fraction of B-cells (HR 2.74, p=0.03).ConclusionsThe presence of TLS in CMMs is associated with improved OS in patients treated with surgery before CBT, but TLS vary widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Importantly, these features have additional prognostic significance, which suggest that some TLS may have regulatory function, while others functioning to support antigen-driven immune responses, depending on the cellular composition and activation status.

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Nayar, Saba, Joana Campos, Charlotte G. Smith, Valentina Iannizzotto, David H. Gardner, Frédéric Mourcin, David Roulois et al. „Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology“. Proceedings of the National Academy of Sciences 116, Nr. 27 (18.06.2019): 13490–97. http://dx.doi.org/10.1073/pnas.1905301116.

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Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.

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Yu, Jinglu, Yabin Gong, Xiaowei Huang und Yufang Bao. „Prognostic and therapeutic potential of gene profiles related to tertiary lymphoid structures in colorectal cancer“. PeerJ 12 (31.10.2024): e18401. http://dx.doi.org/10.7717/peerj.18401.

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The role of tertiary lymphoid structures (TLS) in oncology is gaining interest, particularly in colorectal carcinoma, yet a thorough analysis remains elusive. This study pioneered a novel TLS quantification system for prognostic and therapeutic response prediction in colorectal carcinoma, alongside a comprehensive depiction of the TLS landscape. Utilizing single-cell sequencing, we established a TLS score within the Tumor Immune Microenvironment (TIME). Analysis of tertiary lymphoid structure-related genes (TLSRGs) in 1,184 patients with colon adenocarcinoma/rectum adenocarcinoma (COADREAD) from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases led to the identification of two distinct molecular subtypes. Differentially expressed genes (DEGs) further segregated these patients into gene subtypes. A TLS score was formulated using gene set variation analysis (GSVA) and its efficacy in predicting immunotherapy outcomes was validated in two independent cohorts. High-scoring patients exhibited a ‘hot’ immune phenotype, correlating with enhanced immunotherapy efficacy. Key genes in our model, including C5AR1, APOE, CYR1P1, and SPP1, were implicated in COADREAD cell proliferation, invasion, and PD-L1 expression. These insights offer a novel approach to colorectal carcinoma treatment, emphasizing TLS targeting as a potential anti-tumor strategy.

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Gonzalez, Ricardo A. Chaurio, Kyle K. Payne, Carmen Maria Anadon Galindo, Tara Lee Costich, Carly Harro, Subir Birwas, Kristen Rigolizzo et al. „Satb1 deficiency licenses TFH-differentiation and Tertiary Lymphoid Structure formation in cancer“. Journal of Immunology 204, Nr. 1_Supplement (01.05.2020): 89.2. http://dx.doi.org/10.4049/jimmunol.204.supp.89.2.

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Abstract Tertiary Lymphoid Structures (TLS) are commonly identified in human tumors with improved outcome, but how they are orchestrated remains elusive. Here we show that silencing of the master genomic organizer Satb1 results in enhanced antigen-specific T Follicular Helper (TFH) differentiation. Increased TFH thereby promoted antigen-specific intra-tumoral CD19+B220+ B cell responses and spontaneous TLS assembly upon ovarian tumor challenge. Mechanistically, Satb1 deficiency drives increased TFH formation through de-repression of ICOS and PD-1. Accordingly, TGF-β1-driven downregulation of Satb1 licenses activated human CD4+ T-cells for enhanced antigen-specific T Follicular Helper (TFH) differentiation. Furthermore, Satb1 deficiency abrogates the generation of PD-1highCXCR5+Foxp3+ T Follicular Regulatory (TFR) cells during the TFH differentiation process. Importantly, functional TFH cell accumulation, in the absence of Satb1 specifically in CD4+ T cells, resulted in corresponding isotype-switched B cell responses and spontaneous formation of TLS, while B cell depletion accelerated malignant progression. Our results indicate that the formation of TLS in cancer depends on enhanced B cell responses driven by TFH cells generated through Satb1 down-regulation.

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Thelen, M., MA García-Márquez, T. Nestler, S. Wagener-Ryczek, J. Lehmann, E. Staib, F. Popp et al. „P03.03 Organization, function and gene expression of tertiary lymphoid structures in PDAC resembles lymphoid follicles in secondary lymphoid organs“. Journal for ImmunoTherapy of Cancer 8, Suppl 2 (Oktober 2020): A23.1—A23. http://dx.doi.org/10.1136/jitc-2020-itoc7.43.

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BackgroundSecondary lymphoid organs (SLO) are involved in induction and enhancement of anti-tumor immune responses on different tumor entities. Recent evidence suggests that anti-tumor immune responses may also be induced or enhanced in the tumor microenvironment in so called tertiary lymphoid structures (TLS). It is assumed that TLS represent a hotspot for T cell priming, B cell activation, and differentiation, leading to cellular and humoral anti-tumor immune response.MethodsFFPE-slides of 120 primary pancreatic ductal adenocarcinoma (PDAC) patients were immunohistochemically (IHC) stained for CD20, CD3, CD8 and HLA-ABC to analyze spatial distribution of tumor-infiltrating lymphocytes. 5-color immunofluorescence staining was performed to further investigate structural components of TLS in comparison to lymphoid follicles in SLOs. Microscope-based laser microdissection and Nanostring-base RNA expression analysis were used to compare gene expression in PDAC, TLS, SLOs and normal pancreatic tissue.ResultsTLS were frequently detected in PDAC and were mainly localized along the invasive tumor margin. In less than 10% of the cases TLS were infiltrating the tumors. Interestingly, 20% of the patients had no TLS. Results of TLS will be correlated with clinical parameters, Immunoscore and immune escape mechanisms. 5-color Immunofluorescence staining revealed similar organization and function of TLS and SLO. Finally, gene expression analyzed by Nanostring revealed largely overlapping expression patterns in TLS and SLO.ConclusionsThe results clearly demonstrate close similarities between SLO and TLS in terms of composition, distribution and gene expression Patterns.Disclosure InformationM. Thelen: None. M.A. García-Márquez: None. T. Nestler: None. S. Wagener-Ryczek: None. J. Lehmann: None. E. Staib: None. F. Popp: None. F. Gebauer: None. P. Lohneis: None. M. Odenthal: None. S. Merkelbach-Bruse: None. C. Bruns: None. K. Wennhold: None. M. von Bergwelt-Baildon: None. H.A. Schlößer: None.

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Zou, Yi, Jing Zhao, Fengbo Huang, Xueping Xiang und Yang Xia. „Decreased Tertiary Lymphoid Structures in Lung Adenocarcinomas with ALK Rearrangements“. Journal of Clinical Medicine 11, Nr. 19 (08.10.2022): 5935. http://dx.doi.org/10.3390/jcm11195935.

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Purpose: This study sought to characterize the tumor immune microenvironment (TIME) of lung adenocarcinomas with ALK rearrangements (ALK+ LUAD), which responds poorly to immune checkpoint inhibitors (ICIs) therapy. Materials and methods: Immune score evaluation and immunohistochemical (IHC) validation of B cells, cytotoxic, helper, regulatory T cells, dendritic cells, and tumor-associated macrophages were performed on the TCGA cohort and the whole tissue sections of our matched surgical samples, respectively, between ALK+ and ALK− LUAD. The formation and spatial organization of TLS, intra- and extra-TLS immune cell features, and tumor PD-L1 expression were analyzed independently. Results: Immune scores and TLS-signature gene levels were found to be lower in ALK+ TCGA LUAD. Quantitative IHC comparison confirmed the lower densities of TLS (0.10/mm2 vs. 0.34/mm2, p = 0.026) and intra-TLS immune cells (CD4+ helper T cells: 57.65/mm2 vs. 274.82/mm2, p = 0.026; CD8+ cytotoxic T cells: 22.46/mm2 vs. 172.83/mm2, p = 0.018; and CD20+ B cells: 36.08/mm2 vs. 207.29/mm2, p = 0.012) in ALK+ surgical samples. The TLS formation was negatively correlated with tumor progression in ALK+ tumors. The proportion of intra-TLS CD8+ cytotoxic T cells was the independent protective factors of node metastasis (HR: 0.599, 95% CI: 0.414–0.868, p = 0.007), and the density of intra-TLS CD20+ B cells was the independent protective factor of pStage (HR: 0.641, 95% CI: 0.446–0.922, p = 0.016). Tumors with intratumoral TLS showed significantly higher expression of PD-L1 (p = 0.029). Conclusion: ALK+ LUAD harbored a cold TIME featured by decreased TLS formation, which closely correlated to tumor progression and might contribute to the poor efficiency of ICIs.

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Sofronii, Doïna, Francine Padonou, Mireille Langouo, Noemie Thomas, Anais Boisson, Alexandre De Wind, Denis Larsimont, Ahmad Awada, Soizic Garaud und Karen Willard-Gallo. „Abstract 4618: Biomarkers of functionally active tertiary lymphoid structures in human breast cancer“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 4618. http://dx.doi.org/10.1158/1538-7445.am2023-4618.

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Abstract The clinical relevance of tumor infiltrating lymphocytes (TIL) in breast cancer (BC) is now widely accepted and being implemented in clinical practice. Our lab previously demonstrated that 60% of BC organize some of their TIL in tertiary lymphoid structures (TLS). TLS have been detected in a wide variety of solid tumors with their prognostic value and importance in the response to immunotherapy increasingly accepted. Reliable biomarkers to identify and characterize TLS and their immune activities in tumors are needed. The specific aim of this project was to perform a comprehensive analysis across the spectrum of TLS states to identify biomarkers associated with active and inactive TLS, where the former are associated with functional anti-tumor immunity and improved responses to treatment and long-term survival. This study analyzed FFPE tissues from 38 primary untreated HER2+ and triple negative (TN) BC patients. Patients were divided into two groups based on a TLS score evaluating CD3/CD20 and PD-1/Ki-67 dual IHC-stained tumor tissues: 1) BC containing a majority of active TLS (tumors with only active TLS have never been observed), defined by the presence of a germinal center (GCpos ; Ki-67+ follicular B cells) and 2) BC with only inactive TLS (GCneg ; Ki-67− follicular B cells). Controls included normal breast tissues, BC without TLS and lymphoid tissues (reactive tonsils for GCpos and spleens for GCneg TLS). RNA extracts from microdissected tissues (N=100), including active TLS, inactive TLS and lymphoid B follicles, were sequenced. DESeq2 and CIBERSORT were employed to quantify differentially expressed genes and immune cell subpopulations, respectively. Gene Set Enrichment Analysis was used for additional data interpretation and pathway identification. Tumors from patients with active TLS were characterized by increased naïve and plasma B cell TIL compared to tumors with only inactive TLS. Preliminary analysis of the differentially expressed genes in active TLS (vs inactive TLS) revealed upregulation of key B cell differentiation, somatic hypermutation and class switch recombination genes, which paralleled their respective lymphoid controls. These gene upregulations were linked with a GC presence in active TLS. A specific set of immunoglobulin genes were also differentially expressed in active TLS. Continued analysis of the TLS data, including their cellular composition, location, maturation and functionality, along with data confirmation (RT-PCR and multiplex IHC), and assessment of their functional and clinical relevance is ongoing. Our preliminary results suggest that active B cell differentiation and Ig production contribute to TLS functionality. In lymphoid tissues, the GC plays important roles in orchestrating the molecular and cellular programs of humoral immunity. Our data suggest that active GC-containing TLS foster an immune microenvironment in BC that favors positive clinical outcomes. Citation Format: Doïna Sofronii, Francine Padonou, Mireille Langouo, Noemie Thomas, Anais Boisson, Alexandre De Wind, Denis Larsimont, Ahmad Awada, Soizic Garaud, Karen Willard-Gallo. Biomarkers of functionally active tertiary lymphoid structures in human breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4618.

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Luo, Ran, Dan Chang, Nanhui Zhang, Yichun Cheng, Shuwang Ge und Gang Xu. „T Follicular Helper Cells in Tertiary Lymphoid Structure Contribute to Renal Fibrosis by IL-21“. International Journal of Molecular Sciences 24, Nr. 16 (08.08.2023): 12535. http://dx.doi.org/10.3390/ijms241612535.

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Tertiary lymphoid structure (TLS) represents lymphocyte clusters in non-lymphoid organs. The formation and maintenance of TLS are dependent on follicular helper T (TFH) cells. However, the role of TFH cells during renal TLS formation and the renal fibrotic process has not been comprehensively elucidated in chronic kidney disease. Here, we detected the circulating TFH cells from 57 IgAN patients and found that the frequency of TFH cells was increased in IgA nephropathy patients with renal TLS and also increased in renal tissues from the ischemic-reperfusion-injury (IRI)-induced TLS model. The inducible T-cell co-stimulator (ICOS) is one of the surface marker molecules of TFH. Remarkably, the application of an ICOS-neutralizing antibody effectively prevented the upregulation of TFH cells and expression of its canonical functional mediator IL-21, and also reduced renal TLS formation and renal fibrosis in IRI mice in vivo. In the study of this mechanism, we found that recombinant IL-21 could directly promote renal fibrosis and the expression of p65. Furthermore, BAY 11-7085, a p65 selective inhibitor, could effectively alleviate the profibrotic effect induced by IL-21 stimulation. Our results together suggested that TFH cells contribute to TLS formation and renal fibrosis by IL-21. Targeting the ICOS-signaling pathway network could reduce TFH cell infiltration and alleviate renal fibrosis.

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Dissertationen zum Thema "Tertiary lymphoid structure (TLS)"

Houel, Ana. „Étude de l’induction de structures lymphoïdes tertiaires, par virothérapie oncolytique, pour stimuler l’immunité antitumorale endogène“. Electronic Thesis or Diss., Sorbonne université, 2024. http://www.theses.fr/2024SORUS232.

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Les structures lymphoïdes tertiaires (TLS) sont des agrégats organisés de cellules immunitaires qui se développent dans les tissus non-lymphoïdes à la suite d'une inflammation chronique. Les TLS matures, dont l'organisation est proche de celle d'un ganglion, sont associées à un bon pronostic dans les cancers à tumeurs solides et servent de prédicteur efficace de la réponse des patients traités par immunothérapie. Notre objectif a été d'étudier la virothérapie oncolytique comme stratégie pour induire des TLS dans le microenvironnement tumoral (TME) afin d'intensifier les réponses antitumorales.Les virus oncolytiques (OV) ont la capacité d'infecter et de se répliquer spécifiquement dans les cellules cancéreuses, induisant leur lyse directe ainsi que leur destruction par le système immunitaire via la mort immunogène. Nous supposons que la modulation du microenvironnement tumoral suite à l'infection par des OV, ainsi que la production locale de chimiokines exprimées par ces derniers, pourrait favoriser la néogenèse de TLS et amplifier les réponses antitumorales.Mes travaux ont alors consisté à générer et caractériser des virus de la vaccine oncolytiques (oVV) recombinants, armés avec trois chimiokines, CCL20, CCL21 et CXCL13, que nous supposons impliquées dans la néogenèse de TLS.J'ai observé que l'expression des chimiokines par les oVV recombinants n'affectait pas leurs propriétés oncolytiques et que les chimiokines étaient bien fonctionnelles in vitro. Bien que la réplication des oVV fût réduite dans les modèles murins syngéniques, j'ai détecté les chimiokines murines dans les tumeurs infectées avec les oVV armés ainsi que la formation d'agrégats immunitaires dans les modèles de tumeur chaude. Néanmoins, aucune amélioration thérapeutique n'a été observée avec l'oVV armé avec les chimiokines par rapport au virus non armé.J'ai alors étudié la capacité de TLS induites par un oVV, à établir des réponses antitumorales, dans le modèle orthotopique TC-1 luc qualifié de chaud. Dans ce modèle, j'ai observé que l'administration intranasale de l'oVV induisait plus de TLS que l'administration d'un virus de la vaccine non oncolytique, le MVA. De plus, j'ai observé que les TLS induites par l'infection virale par le MVA n'étaient pas associées à une réponse antitumorale alors que j'ai détecté à long terme la présence de lymphocytes T spécifiques antitumoraux et un contrôle de la tumeur pulmonaire chez une souris infectée par l'oVV. Ainsi, nous supposons que les propriétés oncolytiques des oVV peuvent induire des TLS efficaces contre les tumeurs.Pour favoriser la réplication des oVV et l'expression des chimiokines, ainsi que pour faciliter l'observation des réponses antitumorales tardives avec des cinétiques de croissance tumorale plus lentes, nous avons évalué l'efficacité d'une souche recombinante armée avec les trois chimiokines humaines (oVV-3hCK) dans un modèle de souris humanisées HIS-NXG greffées avec des tumeurs humaines.Dans ce modèle, les oVV (oVV-3hCK et oVV non armé) ont été particulièrement efficaces, ce qui n'a pas permis d'observer des différences d'efficacité thérapeutique entre les deux souches. Néanmoins, une augmentation significative de l'infiltration en cellules immunitaires CXCR5+ et en lymphocytes T et B naïfs a été observée dans les tumeurs infectées avec l'oVV-3hCK, confirmant l'activité chimiotactique des chimiokines et laissant supposer la présence de TLS dans les tumeurs.En conclusion, mes travaux de thèse ont confirmé que les trois chimiokines CCL20, CCL21 et CXCL13 exprimées par un oVV sont capables d'induire des agrégats immunitaires (ou TLS) dans le TME, et ont démontré la pertinence de cette stratégie pour améliorer la réponse antitumorale à long terme
Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop in non-lymphoid tissues as a result of chronic inflammation. Mature TLS, which resemble lymph nodes in their organization, are associated with favorable prognoses in solid tumor cancers and serve as effective predictors of patient responses to immunotherapy. Our objective was to investigate oncolytic virotherapy as a strategy to induce TLS in the tumor microenvironment (TME) to enhance anti-tumor responses.Oncolytic viruses (OV) have the ability to specifically infect and replicate within cancer cells, inducing their direct lysis as well as their destruction by the immune system through immunogenic cell death. We hypothesize that the modulation of the TME following OV infection, along with the local production of chemokines expressed by these viruses, could promote TLS neogenesis and amplify anti-tumor responses.My work involved generating and characterizing recombinant oncolytic vaccinia viruses (oVV) armed with three chemokines, CCL20, CCL21, and CXCL13, which we hypothesize are involved in TLS neogenesis.I observed that the expression of chemokines by the recombinant oVVs did not affect their oncolytic properties and that the chemokines were functional in vitro. Although the replication of the oVVs was reduced in syngeneic murine models, I detected the murine chemokines in tumors infected with the armed oVVs and observed the formation of immune aggregates in hot tumor models. However, no therapeutic improvement was observed with the chemokine-armed oVV compared to the non-armed virus.I then studied the ability of TLS induced by an oVV to establish anti-tumor responses in the hot orthotopic TC-1 luc model. In this model, I observed that intranasal administration of the oVV induced more TLS than administration of a non-oncolytic vaccinia virus, MVA. Furthermore, I observed that TLS induced by MVA infection were not associated with an anti-tumor response, whereas I detected long-term presence of tumor-specific T lymphocytes and tumor control in the lungs of a mouse infected with oVV. Thus, we hypothesize that the oncolytic properties of oVVs can induce TLS that are effective against tumors.To promote oVV replication and chemokine expression, as well as to facilitate the observation of late anti-tumor responses with slower tumor growth kinetics, we evaluated the efficacy of a recombinant strain armed with the three human chemokines (oVV-3hCK) in a HIS-NXG humanized mouse model grafted with human tumors.In this model, the oVVs (oVV-3hCK and non-armed oVV) were particularly effective, making it difficult to observe differences in therapeutic efficacy between the two strains. Nonetheless, a significant increase in the infiltration of CXCR5+ immune cells and naïve T and B lymphocytes was observed in tumors infected with oVV-3hCK, confirming the chemotactic activity of the chemokines and suggesting the presence of TLS in the tumors.In conclusion, my thesis work confirmed that the three chemokines CCL20, CCL21, and CXCL13 expressed by an oVV are capable of inducing immune aggregates (or TLS) in the TME, and demonstrated the relevance of this strategy to improve long-term anti-tumor responses

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Devi, Priyanka. „Role and prognostic importance of regulatory T cells in lung cancer patients, according to the presence of tertiary lymphoid structures“. Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066345/document.

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Une tumeur est un environnement complexe comprenant à la fois des composants immunitaires et non immunitaires. Dans notre équipe, nous avons démontré précédemment le rôle des structures lymphoïdes tertiaires (TLS) dans les cancers du poumon, dans la génération de réponses anti-tumorales protectrices. Cependant, les tumeurs peuvent se développer en utilisant des mécanismes d’immunosuppression tels que l’infiltration des cellules T régulatrices (Tregs) dans le microenvironnement tumoral. Cette thèse a étudié le mécanisme présumé des Tregs dans la régulation des réponses immunitaires dans le cancer du poumon. Cette étude démontre la présence de Tregs FoxP3+ dans les TLS aussi bien que dans les autres régions tumorales. Les Tregs infiltrant la tumeur (Ti-Tregs) présentent un phénotype de lymphocytes T à mémoire centrale, et effecteur mémoire. Ces cellules expriment un vaste répertoire de molécules d’activation et de « chekpoints » immunologiques. L’analyse de l’expression des gènes et des résultats de cytométrie en flux a montré que les Tregs expriment des marqueurs de co-stimulation et de co-inhibition. Une forte densité de Ti-Tregs dans les TLS ou les autres régions tumorales, est associée à une faible survie des patients. Lorsqu’on combine ce résultat avec la densité de DC matures ou lymphocytes B associés aux TLS ou CD8+, un groupe de patients présentant de faible densités de ces cellules mais de fortes densités en Tregs a le pronostic le moins favorable avec le plus grand risque de décès. Les Tregs créent un environnement immunosuppresseur dans les cancers pulmonaires. Ce mécanisme pourrait être une explication de la réduction observée de la survie de ces patients
Tumor comprise complex niche of the immune and non-immune components. The complex interaction between the tumor cells with its environment turns into either eradication or the growth and metastasis of the tumors. We have previously demonstrated the role of TLS (tertiary lymphoid structures) in lung tumors, in protective anti-tumor responses. Despite of this, tumors do develop via exploiting the regulatory mechanisms, particularly includes, infiltration of the Tregs (regulatory T cells). The aim of thesis was to study the putative role of Tregs in regulating the immune responses in lung cancer. This study strongly demonstrates the presence of FoxP3+ Tregs in the TLS as well as non-TLS areas of the lung tumors. Tregs mainly exhibit central and effector memory phenotype expressing vast repertoire of the activation and immune checkpoint molecules. The gene expression and flow cytometry data showed that Tregs express the co-stimulatory and inhibitory markers which are known to be involved in the their activation and immune suppression. The high density of the Ti-Tregs either in TLS or in nonTLS areas is associated with the poor survival of the NSCLC patients. When combined with the density of TLS mature DC or B cells or CD8+ T cells, a group of patients with the low DC, B cells and CD8+ T cells but high Tregs densities, had the worst clinical outcome. This allowed, to identify the NSCLC patients with highest risk of death. Thus, it be concluded that the Tregs create the immunosuppressive environment in the lung tumors by acting in both TLS and nonTLS areas of the tumors and thus could be possible reason for the reduced survival of the lung cancer patients

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Kaplon, Hélène. „Rôle des lymphocytes B associés aux structures lymphoïdes tertiaires dans la réponse clinique des patients atteints d’un cancer pulmonaire Cancer-Associated Tertiary Lymphoid Structures, from Basic Knowledge Toward Therapeutic Target in Clinic Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers“. Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS565.

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Le microenvironnement tumoral est un acteur majeur du contrôle immunitaire du développement tumoral. Ce contrôle commence à distance des cellules tumorales, dans le stroma tumoral, au sein de structures appelées structures lymphoïdes tertiaires (TLS), composées d'une zone de lymphocytes B (LB) où se trouvent principalement des lymphocytes B (LB) adjacents à une zone T. Nos précédents résultats ont mis en évidence que la zone B des TLS peut être un site de différenciation des LB en LB mémoires et plasmocytes (PC), sécrétant principalement des IgA et IgG chez les patients atteints de cancer du poumon non à petites cellules (NSCLC). Nous avons donc émis l'hypothèse que ces PC à IgA et IgG peuvent être impliqués dans la génération de réponses immunitaires anti-tumorales. Nous avons démontré que de fortes densités de PC à IgA et IgG sont associées à une meilleure survie chez les patients NSCLC. Une co-localisation entre les PC à IgA et IgG et les LT CD8+stromales a été observée dans le stroma tumoral, suggérant un dialogue entre ces deux types cellulaires pouvant influencer la survie des patients. En effet, nous montrons que la combinaison de fortes densités en PC et LT CD8+ stromales détermine un groupe de patients de meilleur pronostic. L’ensemble de ces résultats fournit de nouvelles connaissances quant au rôle des plasmocytes intra-tumoraux dans le microenvironnement tumoral des patients NSCLC
The tumor microenvironment plays a major role in the immune control of the tumor development. This control starts at a distance from the tumor cells, in the tumor stroma, within structures called tertiary lymphoid structures (TLS), composed of a B-cell zone where B lymphocytes (LB) are mainly found, and a T-cell area that is adjacent to the B-cell zone. Our previous results in non-small cell lung cancer patients (NSCLC) showed that the TLS-associated B-cell zone could be a site of B cell differentiation into memory B cells and IgA and IgG secreting plasma cells (PC). We therefore hypothesized that these IgA and IgG PC could be involved in the generation of the anti-tumor immune response. We demonstrated that high densities of IgA and IgG PC are associated with increased survival of NSCLC patients. A co-localization between PC and stromal CD8+ T cells was observed in the tumor stroma, strongly suggesting the presence of a crosstalk between these immune cell types which positively influences patient survival. Furthermore, we reported that the combination of high density of PC and stromal CD8+ T cell determines the group of patients with the lowest risk of death. Altogether, this study gives new insights in the role of tumor-infiltrating plasma cells in the tumor microenvironment of NSCLC patients

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Buchteile zum Thema "Tertiary lymphoid structure (TLS)"

Klein, Christophe, Priyanka Devi-Marulkar, Marie-Caroline Dieu-Nosjean und Claire Germain. „Development of Tools for the Selective Visualization and Quantification of TLS-Immune Cells on Tissue Sections“. In Tertiary Lymphoid Structures, 47–69. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_4.

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Louveau, Antoine. „Meningeal Immunity, Drainage, and Tertiary Lymphoid Structure Formation“. In Tertiary Lymphoid Structures, 31–45. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_3.

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Devi-Marulkar, Priyanka, Hélène Kaplon, Marie-Caroline Dieu-Nosjean und Myriam Lawand. „Designed Methods for the Sorting of Tertiary Lymphoid Structure-Immune Cell Populations“. In Tertiary Lymphoid Structures, 189–204. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_11.

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Gu-Trantien, Chunyan, Soizic Garaud, Edoardo Migliori, Cinzia Solinas, Jean-Nicolas Lodewyckx und Karen Willard-Gallo. „Quantifying Tertiary Lymphoid Structure-Associated Genes in Formalin-Fixed Paraffin-Embedded Breast Cancer Tissues“. In Tertiary Lymphoid Structures, 139–57. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_9.

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Couillault, Coline, Claire Germain, Bertrand Dubois und Hélène Kaplon. „Identification of Tertiary Lymphoid Structure-Associated Follicular Helper T Cells in Human Tumors and Tissues“. In Tertiary Lymphoid Structures, 205–22. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_12.

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Gutierrez-Chavez, Claudia, Samantha Knockaert, Marie-Caroline Dieu-Nosjean und Jérémy Goc. „Development of Methods for Selective Gene Expression Profiling in Tertiary Lymphoid Structure Using Laser Capture Microdissection“. In Tertiary Lymphoid Structures, 119–37. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_8.

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MacFawn, Ian P., und Tullia C. Bruno. „Tertiary Lymphoid Structure Formation and Function in the Tumor Microenvironment“. In Handbook of Cancer and Immunology, 1–31. Cham: Springer International Publishing, 2024. http://dx.doi.org/10.1007/978-3-030-80962-1_83-1.

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Gutierrez-Chavez, Claudia, Samantha Knockaert, Marie-Caroline Dieu-Nosjean und Jeremy Goc. „Methods for Selective Gene Expression Profiling in Single Tertiary Lymphoid Structure Using Laser Capture Microdissection“. In Methods in Molecular Biology, 107–26. New York, NY: Springer US, 2024. http://dx.doi.org/10.1007/978-1-0716-4184-2_6.

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Klein, Christophe, Priyanka Devi-Marulkar, Marie-Caroline Dieu-Nosjean und Claire Germain. „Advancement of Techniques for Precise Visualization and Quantification of Tertiary Lymphoid Structure-Associated Immune Cells in Tissue Samples“. In Methods in Molecular Biology, 181–203. New York, NY: Springer US, 2024. http://dx.doi.org/10.1007/978-1-0716-4184-2_10.

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Nicolini, Fabio, und Massimiliano Mazza. „The Immune System of Mesothelioma Patients: A Window of Opportunity for Novel Immunotherapies“. In Rare Diseases [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.98617.

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The interplay between the immune system and the pleural mesothelium is crucial both for the development of malignant pleural mesothelioma (MPM) and for the response of MPM patients to therapy. MPM is heavily infiltrated by several immune cell types which affect the progression of the disease. The presence of organized tertiary lymphoid structures (TLSs) witness the attempt to fight the disease in situ by adaptive immunity which is often suppressed by tumor expressed factors. In rare patients physiological, pharmacological or vaccine-induced immune response is efficient, rendering their plasma a valuable resource of anti-tumor immune cells and molecules. Of particular interest are human antibodies targeting antigens at the tumor cell surface. Here we review current knowledge regarding MPM immune infiltration, MPM immunotherapy and the harnessing of this response to identify novel biologics as biomarkers and therapeutics through innovative screening strategies.

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Konferenzberichte zum Thema "Tertiary lymphoid structure (TLS)"

Sonntag, M., C. Brunner und TK Hoffmann. „Analyses of germinal center B cells and tertiary lymphoid structures (TLS) in mouse and human HNSCC“. In Abstract- und Posterband – 90. Jahresversammlung der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie e.V., Bonn – Digitalisierung in der HNO-Heilkunde. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1686078.

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Ukita, Masayo, Junzo Hamanishi, Tsukasa Baba, Ryusuke Murakami, Kaoru Abiko und Masaki Mandai. „Abstract 1021: Clinical significance of tertiary lymphoid structures (TLS) and tumor-infiltrating plasma cells in ovarian cancer“. In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1021.

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Iding, Jeff, Paul VanderLaan, Marcelo Jimenez, José Fernández García-Hierro, Javier Flandes Aldeyturriaga, Erik HFM van der Heijden, Calvin SH Ng et al. „702 Tertiary lymphoid structures (TLS) observed in non-small cell lung cancer (NSCLC) tumors treated with pulsed electric fields“. In SITC 37th Annual Meeting (SITC 2022) Abstracts. BMJ Publishing Group Ltd, 2022. http://dx.doi.org/10.1136/jitc-2022-sitc2022.0702.

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Hamanishi, Junzo, Haruka Suzuki, Akihiko Ueda, Ken Yamaguchi und Masaki Mandai. „SO016/#846 Deep learning for spatial distribution of tertiary lymphoid structures (TLS) and efficacy of immunotherapy for endometrial cancer“. In IGCS 2023 Annual Meeting Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/ijgc-2023-igcs.30.

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Downey, Kira Morgan, Bindu Hegde, Zinal Chheda, Jason Zhang und Hideho Okada. „Abstract 74: Engineering tertiary lymphoid structures for glioblastoma: A novel gene combination promotes therapeutic TLS formation in an immune-competent mouse model of GBM“. In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-74.

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Srivastava, Minu K., Velimir Gayevskiy, Vy Ma, Ivette Estay, Miguel Lopez de Rodas, Barani Kumar Rajendran, Tien Hoang et al. „606 IMpower110: Tertiary lymphoid structures (TLS) and clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with first-line atezolizumab or chemotherapy“. In SITC 38th Annual Meeting (SITC 2023) Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/jitc-2023-sitc2023.0606.

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Guo, Phoebe, Eshed Margalit, Daniel Bear, Dexter Antonio, Yubin Xie, Meena Subramaniam, Lucas Cavalcante et al. „861 Multimodal foundation model of human lung tumors identifies tertiary lymphoid structures (TLS) and reveals novel therapeutic targets that promote anti-tumor immune response“. In SITC 39th Annual Meeting (SITC 2024) Abstracts, A975. BMJ Publishing Group Ltd, 2024. http://dx.doi.org/10.1136/jitc-2024-sitc2024.0861.

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Fontaine, C., G. Van den Eynden, R. de Wind, A. Boisson, V. Renard, H. Van den Bulck, P. Vuylsteke et al. „Abstract P2-08-47: Evaluation of stromal tumor-infiltrating lymphocytes (sTIL) and tertiary lymphoid structures (TLS) in early breast cancer patients with triple negative breast cancer(TNBC) included in a prospective study of neoadjuvant chemotherapy (NAC) with Epirubicin and cyclophosphamide (EC) and carboplatin-paclitaxel (PC) (BSMO 2014-01)“. In Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-p2-08-47.

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Karapetyan, Lilit, Xi Yang, Hong Wang, Cindy Sander, Arivarasan Karunamurthy, John M. Kirkwood und Walter J. Storkus. „Abstract 2683: Serum multiplex analysis of tertiary lymphoid structure-associated chemokines/cytokines in melanoma patients“. In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-2683.

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Liu, Dongyan, Xiang Li, Rajesh Acharya, Ernest M. Meyer, Shelley Reynolds, Ayana Ruffin, Robert L. Ferris, Dario A. A. Vignali, Riyue Bao und Tullia C. Bruno. „Abstract PO-083: Utilizing spatial transcriptomics to elucidate tertiary lymphoid structure heterogeneity in human cancer“. In Abstracts: AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; September 17-18, 2020. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.tumhet2020-po-083.

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Berichte der Organisationen zum Thema "Tertiary lymphoid structure (TLS)"

Lin, Liying, Min Li, Bo Fu, Miaomiao Chu, Song Wang, Bingwu Yang und Dongyan Zhang. Association between tertiary lymphoid structure and HNSCC: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, August 2023. http://dx.doi.org/10.37766/inplasy2023.8.0031.

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