Relevant bibliographies by topics / Tertiary lymphoid structure

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  2. Dissertations / Theses
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Academic literature on the topic 'Tertiary lymphoid structure'

Author: Grafiati
Published: 30 November 2024

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Journal articles on the topic "Tertiary lymphoid structure"

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Cook, Seungho, Haenara Shin, Mi-Kyoung Seo, Dae Seung Lee, and Hongyoon Choi. "Abstract 5420: Deep learning-based mapping of tertiary lymphoid structure scores from H&E images of renal cell carcinoma trained by spatial transcriptomics data." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5420. http://dx.doi.org/10.1158/1538-7445.am2023-5420.

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Abstract Purpose Tertiary lymphoid structures are organized aggregates of immune cells present in the tumor microenvironment (TME) in which novel targets as well as beneficial biomarkers for immunotherapy in cancer were found. Here, we have developed and validated a deep learning model by integrating H&E images of renal cell carcinoma and spatial transcriptomics data to infer spatial mapping of tertiary lymphoid structure scores in TME only using hematoxylin and eosin (H&E) images. Methods A total of 20 H&E images combined with spatial transcriptomics data of renal cell carcinoma were used to develop a model. Tertiary lymphoid structure scores can be acquired for each spot in spatial transcriptomics by geometric mean of the specific gene expression relevant to B cell, T cell, immunoglobulin, fibroblast, complement, and others. A convolutional neural network using H&E image patches as inputs was developed to predict the tertiary lymphoid structure scores from H&E-stained tissue image patches of renal cell carcinoma acquired by different patients. For the external validation, the model estimated the tertiary lymphoid structure scores from H&E-stained tissue image patches of renal cell carcinoma of The Cancer Genome Atlas (TCGA-RCC). Results The tertiary lymphoid structure scores inferred by the model using H&E image patches were significantly correlated with those derived by spatial transcriptomics data as an internal validation (r = 0.68, p < 1e-10). The mean value of the deep learning-based tertiary lymphoid structure scores estimated by the TCGA-RCC tissue images was significantly correlated with the tertiary lymphoid structure scores, T cell enrichment scores and immune cell enrichment scores estimated by bulk RNA-seq data from the corresponding TCGA data. Conclusions A deep learning model to infer spatial tertiary lymphoid structure in the tumor microenvironment using H&E images was developed. As the tertiary lymphoid structure is a key to predict responsiveness of immune checkpoint inhibitors, mapping the score only using H&E images could be clinically translated into image-based biomarkers. This approach can provide objective and flexible deep learning-based models for characterizing tumor microenvironment related to spatial immune distribution. Citation Format: Seungho Cook, Haenara Shin, Mi-Kyoung Seo, Dae Seung Lee, Hongyoon Choi. Deep learning-based mapping of tertiary lymphoid structure scores from H&E images of renal cell carcinoma trained by spatial transcriptomics data. [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 5420.
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Rustamkhanov, R. A., K. Sh Gantsev, and D. S. Tursumetov. "Tertiary Lymphoid Structures and Cancer Prognosis (Brief Review)." Creative surgery and oncology 9, no. 4 (January 24, 2020): 293–96. http://dx.doi.org/10.24060/2076-3093-2019-9-4-293-296.

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This brief review is devoted to the role of tertiary lymphoid structures in oncological processes. A number of research studies carried out over the past ten years have shed light on the functions of such structures in various diseases, as well as their role in the progression of the pathological process or resolution of a disease. The data presented in some research works confirms the relationship between the presence of tumour-specific (tumour-associated) tertiary lymphoid structures and a favourable prognosis in patients with various oncological diseases, which suggests the participation of tertiary lymphoid structures in effective local antitumour immune responses. However, no reliable evidence has so far been obtained that could confirm the contribution of tertiary lymphoid structures to immune processes in vivo, with the available information being largely of a correlative character. It should be emphasized that the clinical significance of tertiary lymphoid structures ranges from a destructive to protective impact, which indicates the need for an improved understanding of the structure and case-specific function of these organs before conducting clinical targeting.
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Robles, Marcel R., Michael Malkowski, and Sandeep Krishnan. "S1842 Tertiary Lymphoid Structure Mimicking Pancreatic Mass." American Journal of Gastroenterology 117, no. 10S (October 2022): e1285-e1286. http://dx.doi.org/10.14309/01.ajg.0000864008.96774.a4.

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Evans, Isabel, and Mi-Yeon Kim. "Involvement of lymphoid inducer cells in the development of secondary and tertiary lymphoid structure." BMB Reports 42, no. 4 (April 30, 2009): 189–93. http://dx.doi.org/10.5483/bmbrep.2009.42.4.189.

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Zhou, Xingwang, Wenyan Li, Jie Yang, Xiaolan Qi, Yimin Chen, Hua Yang, and Liangzhao Chu. "Tertiary lymphoid structure stratifies glioma into three distinct tumor subtypes." Aging 13, no. 24 (December 26, 2021): 26063–94. http://dx.doi.org/10.18632/aging.203798.

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Gorecki, Grace, Lan Gardner Coffman, Sarah E. Taylor, and Tullia C. Bruno. "Tertiary lymphoid structure prevalence and prognostic value in cervical cancer." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 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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Sunyer, J. Oriol, Yasuhiro Shibasali, Fumio Takizawa, Ding Yang, Pierre Boudinot, and Aleksei Krasnov. "IDENTIFICATION OF PRIMORDIAL ORGANIZED LYMPHOID STRUCTURE IN THE SPLEEN OF TELEOST FISH." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 92.40. http://dx.doi.org/10.4049/jimmunol.204.supp.92.40.

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Abstract Induction of adaptive immune responses in higher vertebrate species occur within organized lymphoid structures (e.g. lymph nodes, Peyer’s patches). It has been proposed that such structures emerged throughout evolutionary time with the goal to maximize encounters between antigens, antigens-presenting cells and B-T lymphocytes. Fish lack such structures and thus, it remains unknown how and where antigen-specific immunoglobulin responses are induced in these species. To understand how systemic immune responses are induced in teleost lymphoid organs, Rainbow Trout were immunized with several soluble protein antigens. Overall, our results identified the spleen as the major site for CD4+ T and IgM+ B cell proliferation in systemic lymphoid organs upon immunization. The proliferating splenic IgM+ B cells were frequently observed as clusters in the vicinity of melano-macrophage centers. Moreover, in these areas we observed aggregates of B and T lymphocytes with a loose organized structure reminiscent of the cellular architecture frequently associated with tertiary lymphoid organs. Laser dissection microdissection of these areas enabled us to evaluating the immunoglobulin IgM repertoires within these structures upon immunization. Critically, repertoire analysis identified processes of antigen-specific B cell clonal expansion. In conclusion, these data points to the previously unrecognized existence of primordial semi-organized lymphoid tissue in the spleen of teleost fish in which adaptive IgM immune responses are induced. Our findings provide strong evidence that the induction of antigen-specific immune responses in all bony vertebrates requires the formation of organized or semi-organized lymphoid structures.
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HAYASE, SHIMON, NORIKATSU MIYOSHI, SHIKI FUJINO, MASAYOSHI YASUI, MASAYUKI OHUE, SOICHIRO MINAMI, SHINYA KATO, et al. "Fibroblast Activation Protein and Tertiary Lymphoid Structure in Colorectal Cancer Recurrence." Anticancer Research 42, no. 12 (December 2022): 5897–907. http://dx.doi.org/10.21873/anticanres.16099.

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van der Leun, Anne M. "Tertiary lymphoid structure formation: A matter of tumor-immune co-evolution." Molecular Immunology 175 (November 2024): 143–45. http://dx.doi.org/10.1016/j.molimm.2024.09.012.

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Denton, Alice E., Silvia Innocentin, Edward J. Carr, Barry M. Bradford, Fanny Lafouresse, Neil A. Mabbott, Urs Mörbe, et al. "Type I interferon induces CXCL13 to support ectopic germinal center formation." Journal of Experimental Medicine 216, no. 3 (February 5, 2019): 621–37. http://dx.doi.org/10.1084/jem.20181216.

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Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection–induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.
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Dissertations / Theses on the topic "Tertiary lymphoid structure"

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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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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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Le, Rochais Marion. "Cancer colorectal : apport pronostique de l’étude pathomique du microenvironnement tumoral. Focus sur les structures lymphoïdes tertiaires." Electronic Thesis or Diss., Brest, 2024. http://www.theses.fr/2024BRES0044.

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Le cancer colorectal est devenu un défi majeur pour les systèmes de santé en raison de sa prévalence croissante et de son impact sur la qualité de vie des patients. L'analyse anatomopathologique des prélèvements de cancer colorectal, désormais enrichie de données de pathologie moléculaire, est cruciale pour orienter le traitement des patients. Malgré les avancées dans les outils pronostiques et les traitements, les interactions entre les cellules tumorales et immunitaires du microenvironnement tumoral ne sont souvent pas évaluées de manière exhaustive en pratique diagnostique quotidienne. Cette thèse aborde l'importance de l’étude du microenvironnement tumoral dans le cancer colorectal et notamment la nécessité de mieux comprendre le rôle de structures y résidant, les structures lymphoïdes tertiaires (TLS). Les nouvelles techniques telles que la pathologie digitale et l'immunomarquage multiplexe offrent des perspectives pour une analyse plus approfondie et accessible de ce microenvironnement. Ce travail de thèse s’est donc intéressé à caractériser les TLS par imagerie multiplexe, développer des stratégies d'analyse pathomique et explorer leurs corrélations cliniques pour proposer un score utilisable en routine clinique. Ce travail vise à fournir des critères diagnostiques et pronostiques robustes, implémentables dans les services numérisés de pathologie pour guider les décisions thérapeutiques dans le cancer colorectal, contribuant ainsi à une meilleure prise en charge des patients
Colorectal cancer has become a major challenge for healthcare systems today due to its increasing prevalence and its impact on patients' quality of life. The anatomopathological analysis of colorectal cancer specimens, now enriched with molecular pathology data, is crucial for guiding patient treatment. However, despite advances in prognostic tools and treatments, interactions between tumor and immune cells in the tumor microenvironment are often not thoroughly evaluated in daily diagnostic practice. This thesis addresses the importance of studying the tumor microenvironment in colorectal cancer, particularly the need to better understand the role of residing structures, tertiary lymphoid structures (TLS). New techniques such as digital pathology and multiplex immunostaining offer perspectives for a more in-depth and accessible analysis of this microenvironment. Therefore, this thesis focused on characterizing TLS through multiplex imaging, developing pathomic analysis strategies, and exploring their clinical correlations to propose a clinically applicable score. This work aims to provide robust diagnostic and prognostic criteria, implementable in digitized pathology services to guide therapeutic decisions in colorectal cancer, thereby contributing to better patient management
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Lucchesi, Davide. "Development and description of a novel inducible model of salivary gland inflammation in C57BL/6 mice characterised by tertiary lymphoid structures, autoimmunity and exocrine dysfunction." Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8565.

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The accumulation of leukocytes in non-lymphoid tissues and their structural organization into tertiary lymphoid structures (TLS), a process known as ectopic lymphoid neogenesis (ELN), is observed in response to chronic inflammation and in the target organ of several autoimmune diseases. TLS strongly resemble secondary lymphoid organs with specialised high-endothelial venules (HEV), segregated B/T cell areas and presence of follicular dendritic cells (FDC) networks promoting in situ affinity maturation of the antibody response. TLS have been associated with a growing number of autoimmune conditions and usually their presence is prognostic for undesirable disease progression. In Sjögren’s syndrome (SS), an autoimmune disease affecting the salivary and lachrymal glands leading to exocrine dysfunction, TLS develop in the salivary glands (SG) of around one-third of the patients. The immunobiology of the SG and the pathogenesis of SS have been poorly clarified and to date a robust and reproducible inducible animal model of SS and TLS in the SG is still absent. In my PhD, I developed and validated a novel inducible model of ELN in murine SG that also reproduces several features of SS. The retrograde administration of a replication-deficient adenovirus (AdV) in the SGs of wild-type C57Bl/6 mice was able to induce within three weeks fully formed TLS that displayed B/T cell segregation, FDC networks, HEVs and were positive for markers of germinal centres. Moreover, the AdV-treated mice showed a significant reduction of salivary flow and in 75% of the cases development of anti-nuclear antibodies.
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Migliori, Edoardo. "The importance of CD4+ follicular helper T cells and tertiary lymphoid structures in the anti-tumor immune response to breast cancer." Doctoral thesis, Universite Libre de Bruxelles, 2017. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/258252.

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Breast cancer (BC) is the most common cancer in women. It is a highly heterogeneous disease in terms of histology, therapeutic response and patient outcomes. Early and accurate detection of breast cancer is crucial as the patient prognosis varies greatly depending on the diagnosis of the disease. Patient outcomes have been linked to the presence of tumor infiltrating lymphocytes (TIL) in solid tumors. In human BC, higher TIL infiltration is associated with a better prognosis and also predicts relevant responses to pre-operative chemotherapy. TIL are primarily composed of T cells, albeit around 20% of BC patients (pts) show significant B cell infiltration, and can organize in tertiary lymphoid structures (TLS) located in the peritumoral stroma, which are associated with survival in HER2+ and triple negative BC patients. Further, these studies revealed that CD4+ follicular helper T (Tfh) cells producing CXCL13 were specifically associated with peritumoral TLS. CXCL13 is an important B cell chemoattractant whose function is to recruit B cells to the germinal center (GC) in secondary lymphoid organs and TLS, where they can mature and differentiate into memory or antibody-producing B cells. The principal objective of this thesis project was to investigate the role of CXCL13 and Tfh cells play in the development and/or maintenance of GC-like structures in BC-associated TLS.Further understanding of the factors that promote TLS formation in vivo could provide important insight for treatment decisions in BC. CXCL13 expression was originally identified as an important signal associated with TLS that was predictive for patient outcomes. We investigated factors capable of inducing CXCL13 expression in CD4+ T cells isolated from peripheral blood, using flow cytometry analysis. Treatment with TGFβ1 alone, or together with several cytokines (IL12, IL21, and in particular IL2 blockade), increased CXCL13 expression in activated CD4+ T cells. Similar to our characterization of Tfh TIL in fresh tumor tissues, these CXCL13-producing CD4+ T cells were CXCR5 negative and expressed the Tfh markers PD-1 and ICOS. The positive correlation, in treated cells and fresh TIL, between CXCL13-producing CD4+ T cells and FoxP3-expressing regulatory CD4+ T cells, and the diminished chemokine production upon depletion of the latter population, suggest a possible positive relationship between regulatory CD4+ T cells and CXCL13-producing CD4+ T cells.We then derived a GC-associated B cell gene signature for integration in our previously published Tfh cell gene signature, including CXCL13 gene. The combined GC gene signature was tested for its ability to sensitively detect BC-associated TLS using a qRT-PCR-based assay on two different cohorts, a primary BC set (n=83) and a retrospective series (n=52) of formalin-fixed paraffin-embedded (FFPE) BC tissues. These data revealed a correlation between gene signature expression and the extent of TLS scored by trained pathologists on dual-immunohistochemistry stained (CD3+CD20 for T and B cells, respectively) FFPE tissue sections. In addition, the high GC signature expression predicted better overall and disease-free survival of BC pts in our retrospective BC cohort, as well as in public microarray data.This thesis research has demonstrated that CXCL13-producing CD4+ T cells lacking CXCR5 differentiate and exert their function in IL-2-limited but TGF-β1-rich conditions. Furthermore, we developed a GC-associated gene signature able to detect TLS in BC and predict BC pts better survival.
Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
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7

Geyer, Elisabeth. "Akkumulation infiltrierender 6-sulfo LacNAc+ dendritischer Zellen im Kolonkarzinom." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-226707.

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Das kolorektale Karzinom (KRK) zählt zu den immunogenen Tumoren und zeichnet sich durch eine ausgeprägte Infiltration von verschiedenen Immunzell-Populationen aus. Dabei scheinen insbesondere CD8+ T-Lymphozyten und CD4+ T-Helfer-Zellen Typ 1 das Tumorwachstum zu beeinflussen und spielen somit eine zunehmende Rolle als prognostische Marker. Dementsprechend ergaben sich mehrere Hinweise, dass eine hohe Frequenz dieser beiden T-Zell-Populationen in KRK-Geweben mit einer erhöhten Überlebensrate assoziiert ist. Diese neuen Erkenntnisse könnten zukünftig in die Klassifikation des KRKs einfließen und therapeutische Entscheidungen beeinflussen. Im Gegensatz zu Tumor-infiltrierenden T-Zellen ist jedoch über die Frequenz und die Eigenschaften von nativen humanen dendritischen Zellen (DCs) in Kolonkarzinom-Geweben und deren mögliche Rolle in der immunologischen Abwehr von Tumoren nur sehr wenig bekannt. Als professionelle antigenpräsentierende Zellen spielen DCs eine Schlüsselrolle bei der Induktion und Aufrechterhaltung einer Tumor-gerichteten Immunantwort und können dadurch die Tumorentwicklung wesentlich beeinflussen. Daher wurden im Rahmen dieser Dissertation erstmalig Frequenz, Verteilung, Reifestatus und Zytokinexpression von 6-sulfo LacNAc+ (slan) DCs in Kolonkarzinom-Geweben sowie in korrespondierenden tumorfreien Kolon-Geweben untersucht. SlanDCs stellen eine große Subpopulation von humanen Blut-DCs dar, die nach Aktivierung hohe Konzentrationen von verschiedenen proinflammatorischen Zytokinen sezernieren. Darüber hinaus sind sie effizient in der Lage, die antitumoralen Eigenschaften von CD8+ T-Lymphozyten und CD4+ T-Helfer-Zellen sowie von Natürlichen Killer-Zellen zu fördern. Ausgehend von diesen Eigenschaften könnten slanDCs einen Beitrag zur Immunabwehr des Kolonkarzinoms leisten und somit das Tumorwachstum beeinflussen. Im Rahmen dieser Arbeit wurde zunächst mit Hilfe immunhistochemischer Färbungen der Nachweis von slanDCs in Kolonkarzinom-Geweben erbracht. In diesem Zusammenhang konnte eine höhere Frequenz von slanDCs in Kolonkarzinom-Geweben (Mittelwert: 16,69 slanDCs/mm2, n=38) im Vergleich zu den korrespondierenden tumorfreien Geweben (Mittelwert: 9,25 slanDCs/mm2, n=38) detektiert werden. Des Weiteren wurde eine höhere Dichte von infiltrierenden slanDCs in Kolonkarzinom-Gewebeproben (Mittelwert: 18,85 slanDCs/mm2, n=20) im Vergleich zu plasmazytoiden DCs (Mittelwert: 4,86 pDCs/mm2, n=20), welche eine andere Subpopulation von humanen DCs im Blut repräsentieren, nachgewiesen. Ausgehend von diesen Erkenntnissen erfolgten verschiedene Immunfluoreszenzfärbungen zur Untersuchung des Reifestatus und der Zytokinexpression der Kolonkarzinom-infiltrierenden slanDCs. Dabei konnten in allen zehn untersuchten Tumorgeweben CD83-exprimierende slanDCs detektiert werden (Mittelwert: 46,7 % CD83+ slanDCs), was auf einen reifen Phänotyp dieser DCs hinweist. Zudem erfolgte der Nachweis einer Interleukin (IL)-23-Expression in variabler Ausprägung durch infiltrierende slanDCs in zehn von elf analysierten Kolonkarzinom-Geweben (Mittelwert: 33,8 % IL-23+ slanDCs). Dabei stellte sich heraus, dass slanDCs einen wesentlichen Anteil der IL-23-exprimierenden Zellen in einigen untersuchten Gewebeproben darstellen. Eine Expression von Tumornekrosefaktor durch Kolonkarzinom-infiltrierende slanDCs wurde hingegen nur in einer geringen Frequenz detektiert. Weitere Untersuchungen identifizierten slanDCs als neue zelluläre Komponente der T-Zell-Zone von tertiären lymphoiden Strukturen (TLS) der Tumorumgebung des Kolonkarzinoms. Darüber hinaus wies ein deutlicher Anteil der dort lokalisierten slanDCs einen reifen Phänotyp oder eine Expression von IL-23 auf. Ausgehend von diesen neuen Ergebnissen könnten die infiltrierenden slanDCs an der Modulation einer adaptiven Immunantwort in der T-Zell-Zone Kolonkarzinom-assoziierter TLS beteiligt sein und einen Einfluss auf das Tumorwachstum ausüben. Weiterhin könnte die Expression des proinflammatorischen Zytokins IL-23 durch slanDCs im Tumor-umgebenden Stroma und in den TLS eine Induktion IL-17-produzierender Zellen fördern und damit auf eine Beteiligung der slanDCs an einem entzündungsbedingten Fortschreiten der Tumorerkrankung über die IL-23/IL-17-Achse hindeuten. Insgesamt leisten die gewonnenen Erkenntnisse einen Beitrag zum Verständnis der Rolle von humanen nativen DCs im Kolonkarzinom und könnten die Entwicklung neuer immuntherapeutischer Strategien in der Behandlung dieser Tumorerkrankung fördern
Colorectal cancer as an immunogenic tumor is characterized by a marked infiltration of different immune cell populations. Especially CD8+ T-lymphocytes and CD4+ T helper cells type 1 seem to influence tumor growth and therefore play an increasing role as prognostic markers. Thus, it has been shown that high densities of these T cell subsets are associated with improved survival of colorectal cancer patients. These new insights could become part of the classification of colorectal cancer and influence therapeutic decisions. Despite these studies, little is known about the frequency and properties of native human dendritic cells (DCs) in colon cancer tissues and their potential role in antitumor immunity. DCs as professional antigen-presenting cells are critical for the induction and maintenance of antitumor immunity and can essentially influence tumor progression. Thus, the frequency, distribution, maturation, and cytokine expression of 6-sulfo LacNAc+ (slan) DCs in colon cancer tissues as well as in corresponding tumor-free colon specimens were investigated. SlanDCs represent a subset of human blood DCs that secrete large amounts of proinflammatory cytokines upon activation. Furthermore slanDCs are able to efficiently activate CD4+ T cells, tumor-reactive CD8 + T cells, and natural killer cells. Due to these functional properties, slanDCs may contribute to antitumor immunity and may influence tumor growth. Within this doctoral thesis the presence of slanDCs in primary colon cancer samples was immunohistochemically verified. In this context, a higher frequency of slanDCs in colon cancer tissues (mean: 16,69 slanDCs/mm2, n=38) in comparison to the corresponding tumor-free specimens (mean: 9,25 slanDCs/mm2, n=38) could be detected. Moreover, higher frequencies of infiltrating slanDCs in colon cancer tissues (mean: 18,85 slanDCs/mm2, n=20) were detectable compared to plasmacytoid DCs (mean: 4,86 pDCs/mm2, n=20), representing another human blood DC-subset. Based on these results, various immunofluorescence stainings were performed to investigate maturation and cytokine expression of the infiltrating slanDCs. SlanDCs expressing the maturation marker CD83 were detected in all 10 analyzed colon cancer tissues (mean: 46,7% CD83+ slanDCs). In addition, IL-23-expressing slanDCs were present at varying percentages in 10 of 11 evaluated colon cancer samples (mean: 33,8% IL-23+ slanDCs). Interestingly, in several tissues slanDCs represented a marked proportion of all IL-23-expressing cells. However, slanDCs expressing tumor necrosis factor could only be detected in low frequencies in the analyzed colon cancer specimens. Further studies revealed that slanDCs are a novel component of the T-cell zone of colon cancer-associated tertiary lymphoid structures (TLS). A proportion of these TLS-associated slanDCs displays a mature phenotype or express IL-23. These novel findings indicate that slanDCs may modulate adaptive immune responses in the T-cell zone of colon cancer-associated TLS and may contribute to the regulation of tumor progression. Furthermore the IL-23-expressing slanDCs in the tumor-surrounding stroma and the TLS may promote the generation of IL-17-producing cells and may participate in inflammation-related cancer progression mediated by the IL-23/IL-17 axis. These novel observations can help to decipher the role of human native DCs in colon cancer and may have implications for the design of therapeutic strategies against this tumor entity
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8

Giraldo-Castillo, Nicolas. "The Immune Microenvironment in Clear Cell Renal Cell Carcinoma : The heterogeneous immune contextures accompanying CD8+ T cell infiltration in clear cell Renal Cell Carcinoma." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066321/document.

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Dans cette étude, nous avons tenté de décrypter les mécanismes reliant l’augmentation de lymphocytes infiltrant les tumeurs (LIT) T CD8+ et un pronostic clinique défavorable dans le cancer du rein à cellules claires (ccRCC). Pour cela, nous avons déterminé 1) la relation entre le pronostic associé à l'expression d’immune checkpoints et l’infiltrat de cellules dendritiques (DC) et de LT CD8+ et 2) les caractéristiques phénotypiques des LIT T CD8+. L’expression des immune checkpoints a été déterminée par immunohistochimie dans une cohorte de 135 ccRCC. Nous avons constaté que les densités des cellules exprimant CD8, PD-1 et LAG-3 sont corrélées, et associées à une diminution de PFS et OS. Egalement, les patients dont les tumeurs présentent des densités élevées de cellules PD-1+ et PD-L1 et/ou PD-L2 +, ont le taux de survie le plus faible. Des densités élevées de DC immatures isolées dans le stroma tumoral sont associées à une forte expression d’immune checkpoints et à un faible taux de survie chez ces patients. En revanche, les patients présentant un taux de survie prolongé ont une densité élevée de lymphocytes CD8+, des DC matures au sein de structures lymphoïdes tertiaires, ainsi qu’une faible expression d’immune checkpoints. Nous avons analysé les LIT T CD8+ chez 21 patients ccRCC par Cytométrie de Flux. On a trouvé un groupe de patients (8/21) dont les tumeurs sont caractérisées par la surexpression de marqueurs inhibiteurs (PD1 et TIM3) et de d'activation (CD69 et CD38), par l'expansion des cellules T CD8 + mémoires effectrices et un plus grand potentiel d’agressivité. En résumé, nous avons démontré qu’une densité élevée de LIT T CD8+ dans les ccRCC est accompagnée d’une forte expression d’immune checkpoints et d’une réponse immunitaire mal coordonnée dans un sous-groupe de tumeurs agressives
To decipher the potential mechanisms linking increased CD8+ T cell infiltration with an adverse clinical outcome in ccRCC, in this study we determined: 1) the prognosis associated with the expression of immune checkpoints and its coordination with dendritic cell (DC) and CD8+ cell infiltration, and 2) the phenotypic traits of CD8+ tumor infiltrating lymphocytes. The prognosis associated with CD8+ and DC infiltrations, in addition to the expression of immune checkpoints were investigated in a cohort of 135 ccRCC by quantitative immunohistochemistry. We found that the densities of CD8+, PD-1+ and LAG-3+ cells were closely correlated, and independently associated with decreased PFS and OS. In addition, patients whose tumors presented both high densities of PD-1+ cells and PD-L1+ and/or L2+ tumor cells, displayed the worst clinical outcome. High densities of immature DC isolated in the tumour stroma were associated with high expression of immune checkpoints and patients’ poor clinical outcome. In contrast, the presence of mature DC within Tertiary Lymphoid Structures identified, among the tumours with high CD8+-TIL densities, those with low expression of immune checkpoints and prolonged survival. We also investigated the phenotype of freshly isolated CD8+TIL in 21 ccRCC by flow cytometry. We found a group tumors (8/21) characterised by the over-expression of inhibitory (PD-1 and TIM-3) and activation markers (CD69 and CD38), the expansion of the effector memory cell subpopulation (CCR7-CD45RA-), and a trend toward more aggressive features. In summary, we demonstrated that the infiltration with CD8+ TIL in ccRCC is accompanied by the enhanced expression of immune checkpoints and a poorly coordinated immune response in a subgroup of aggressive tumors
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Kurtinović, Andrea. "Exploring the tumor microenvironment to improve immunotherapy for bladder cancer." Thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-366582.

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Bladder cancer, as one of the most common cancer types and with high recurrence risk, is considered a candidate for novel immunotherapy strategies. An important aspect of the research for immunotherapy drug development for bladder cancer is to study the tumor microenvironment (TME) and it’s immune contexture. Besides tumor-infiltrating lymphocytes (TILs) as the main drivers of anti-tumor response, recent studies revealed the importance of tumor-associated tertiary lymphoid structures (TLSs) and high endothelial venules (HEVs) in the TME. Structures similar to these were found to spontaneously form in the orthotopic MB49 model used for bladder cancer research in our group. The aim of this study was to perform a deeper characterization of the TME in this model, by using immunofluorescent staining and microscopy. Specifically, the co-localization of tumor infiltrating lymphocytes (CD8+ and CD4+ T cells, CD19+ B cells), CD11c+ dendritic cells and HEVs along with CCL21 signaling were analyzed within orthotopic MB49 tumors, with and without immune stimulation. The quantification of cells expressing CD8, CD19 and CD11c immune markers, CCL21 levels, vascular density and numbers of HEVs, showed higher densities within the immune-stimulated tumors, indicating a rapid effect of immune stimulation on increasing immune cell infiltration and vascular density after only 24 hours post CpG therapy. Also, the highest frequency of TILs, CCL21 chemokine and vascular density was located in regions of the tumor border indicating that these regions should be studied further in depth as a potential target for entry of cells to the tumor with immunotherapy or as a model of the tumor microenvironment since tumor cell density is maintained high in these locations.
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Gu-Trantien, Chunyan. "Gene expression profiling of CD4+ T cells infiltrating human breast carcinomas identified CXCL13-producing T follicular helper cells associated with tertiary lymphoid structures and better patient outcome." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209474.

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Over the past decade, studies using murine models have led to the demonstration that CD4+ T helper (Th) cells play a critical role in the control of cancer progression. Additional support for their importance comes from the growing body of recent clinical/translational research data demonstrating the importance of tumor-infiltrating T and B lymphocytes in long-term patient survival for various types of cancer, including breast cancer (BC). As the key population coordinating adaptive immune responses, the role(s) played by individual Th subsets in cancer immunity remains largely controversial. The Th1 subset has uniquely been shown to have a clear anti-tumor effect, guiding CD8+ cytotoxic T cells-mediated direct tumor cell lysis through IFN-γ secretion. Although the negative regulatory role played by Treg cells has been extensively studied in cancer, its prognostic value along with that of Th2 and Th17 cells have not been clearly demonstrated in patients. T follicular helper (Tfh) cells, a recently characterized Th subset that plays a primary role in the generation of B cell memory in secondary lymphoid organs, have not been previously described infiltrating solid tumors. The principal objective of this thesis was to perform an in-depth characterization of tumor-infiltrating CD4+ T cells (TIL) and Th subsets in human BC, where very little is currently known.

Using whole genome microarrays, we analyzed the gene expression profiles of TIL relative to their counterparts from the axillary lymph nodes and peripheral blood. Applying a novel approach, we compared TIL profiles with public microarray data for Th subsets, demonstrating: 1) the presence of all major Th subsets (Th1, Th2, Th17, Treg as well as Tfh) in the TIL, 2) the TIL are effector memory rather than central memory cells, 3) the TIL are concomitantly activated and suppressed and 4) TIL from tumors with extensive lymphoid infiltrates are more activated/less suppressed in the TCR/CD3 signaling pathway, producing higher levels and a wider panel of Th cytokines than TIL from minimally-infiltrated tumors.

We also performed in vitro experiments to study tumor microenvironment effects on TIL by treating normal CD4+ T cells from healthy donor blood with primary tumor supernatants (SN). Tumor SN largely reproduces the TIL profile in normal Th cells, totally suppressing their activation and inhibiting their cytokine production. Intriguingly, the highly restricted number of cytokines induced by tumor SN included several tumor-promoting factors, such as IL-8 and TNF. SN from an extensively-infiltrated tumor was found to be less immune-suppressive than SN from minimally-infiltrated tumors. In line with this, TIL from minimally-infiltrated tumors are closer to SN-treated (suppressed) activated donor cells whereas TIL from extensively-infiltrated tumors are more similar to activated cells without SN treatment.

These results led us to further investigate the observed differences between TIL from extensive and minimally-infiltrated tumors. Genes characterizing Th1 and Tfh cells were enriched in the extensively-infiltrated tumors. PD-1hiCD200hi Tfh cells were specifically detected in extensively-infiltrated tumors by flow cytometry and these cells were determined to be the major source of the chemokine CXCL13. Immunohistochemical analysis demonstrated highly-organized tertiary lymphoid structures (TLS) within the tumor, containing a CD4+/CD8+ T cell zone and a B cell zone with reactive germinal centers where Tfh cells and follicular dendritic cells (FDC) are resident. Their presence suggests the origin of an effective memory anti-tumor immune response.

Finally, we generated Tfh- and Th1-specific gene signatures reflecting differences between extensive and minimal TIL and tested their prognostic value in large-patient-scale public data sets. Our Tfh signature predicts better 10-year disease-free survival for all BC subtypes, outperforming the Th1 signature, suggesting that Tfh cells play a more central role than Th1 cells in anti-tumor immunity. CXCL13 is the determinant gene of our Tfh signature, showing particularly strong prognostic power for the HER2+ subtype. Additionally, these signatures also predict a better response to neoadjuvant chemotherapy.

This thesis research has demonstrated that a previously undetected Th subset, Tfh cells, infiltrates solid tumors and shown that their presence signals enhanced anti-tumor immunity.

Durant cette dernière décennie, des travaux menés dans des modèles murins ont permis de mettre en évidence le rôle crucial joué par les lymphocytes T auxiliaires CD4+ (Th) dans le contrôle de la progression des cancers. De plus, de nombreuses études cliniques et/ou translationnelles récentes corroborent ces observations en montrant une corrélation entre l’importance de l’infiltration intra-tumorale par les lymphocytes T et B et la survie à long terme des patients atteints de différents types de cancer, dont le cancer du sein. En tant que chefs d’orchestre de la réponse immune adaptative, les rôles spécifiques des sous-populations des cellules Th restent controversés. Les Th1 sont la seule population exerçant une claire réponse anti-tumorale, qui est liée à la sécrétion d’IFN-γ, une cytokine primordiale à l’action des lymphocytes T cytotoxiques CD8+. Bien que le rôle néfaste des T régulateurs (Treg) a été largement étudié dans le cancer, leur implication pronostique ainsi que celle des Th2 et Th17 n’ont pas encore été clairement démontrées. La présence d’une sous-population de CD4, les T auxiliaires folliculaires (Tfh), cellules clés dans la différenciation des lymphocytes B mémoires au sein des organes lymphoïdes secondaires, n’a jamais été décrite dans les cancers solides. Le but principal de ce travail est de caractériser les sous-populations des lymphocytes T CD4+ infiltrant la tumeur (TIL) en prenant comme modèle le cancer du sein humain. A l’heure actuelle, il existe très peu de données sur les TIL CD4 dans ce type de cancer.

Nous avons d’abord établi le profil génique des TIL en les comparant avec ceux provenant des ganglions axillaires ou du sang périphérique. En appliquant une nouvelle approche, nous avons comparé les profils des TIL avec les données publiques de sous-populations de Th et démontré que :1) toutes les sous-populations de cellules Th (Th1, Th2, Th17, Treg et Tfh) infiltrent la tumeur, 2) les TIL ont un phénotype plus proche de celui des cellules mémoires effectrices que des cellules mémoires centrales, 3) les TIL sont simultanément activés et supprimés et 4) les TIL provenant des tumeurs massivement infiltrées («extensives») par des lymphocytes sont mieux activés et moins supprimés que les TIL des tumeurs peu infiltrées («minimales») dans la voie de signalisation TCR et produisent des cytokines d’une quantité plus élevée et d’une répertoire plus large.

Nous avons également effectué des expériences in vitro pour étudier l’effet de l’environnement tumoral sur les TIL en traitant des CD4 normaux (provenant des donneuses saines) par le surnageant (SN) extrait des tumeurs fraiches. Le SN tumoral induit un profil génique proche de celui des TIL en inhibant l’activation et la production de cytokines de ces cellules stimulées. Curieusement, parmi le peu de cytokines induites par le SN tumoral, des facteurs pro-tumoraux comme IL-8 et TNF sont détectés. Le surnageant provenant d’une tumeur «extensive» est moins immunosuppresseur que ceux des tumeurs «minimales». Conformément, les TIL provenant des tumeurs «minimales» ont un profil génique proche des cellules normales activées et traitées (supprimées) par le SN tumoral tandis que les TIL des tumeurs «extensives» ressemblent aux cellules activées non traitées.

Ces résultats nous avaient guidés à investiguer plus profondément les différences observées entre les TIL des tumeurs «extensives» et «minimales». Les gènes caractéristiques des Th1 et Tfh sont enrichis dans les tumeurs «extensives». Les cellules Tfh PD1hiCD200hi sont spécifiquement détectées par cytométrie de flux dans les tumeurs «extensives» et sont identifiées comme les producteurs principaux de la chimiokine CXCL13. L’examen par immunohistochimie a permis de détecter des structures lymphoïdes tertiaires (TLS) dans la tumeur, composées d’une zone T (CD4 et CD8) et d’une zone B au sein de laquelle se trouve parfois un centre germinatif actif contenant des Tfh et des cellules dendritiques folliculaires (FDC). La présence de ces structures suggère l’origine d’une réponse immune mémoire anti-tumorale.

Finalement, nous avons établi des signatures géniques spécifiques aux Tfh et Th1 et recherché leur impact pronostique dans deux bases de données publiques à grande échelle. Notre signature Tfh est positivement corrélée avec la survie à 10 ans des patientes de tous les sous-types de cancer du sein, et est plus performante que la signature Th1. Ceci suggère que les Tfh pourraient jouer un rôle plus crucial que les Th1 dans la réponse immune anti-tumorale. CXCL13 est le gène déterminant de notre signature Tfh et son expression est fortement associée à une meilleure survie chez les patientes du sous-type HER2+. De plus, ces signatures prévoient également une meilleure réponse à la chimiothérapie néoadjuvante (préopératoire).

Cette étude a démontré qu’une nouvelle sous-population de CD4, les Tfh, infiltre la tumeur solide et leur présence indique l’existence d’une immunité anti-tumorale renforcée.


Doctorat en Sciences biomédicales et pharmaceutiques
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Books on the topic "Tertiary lymphoid structure"

1

Dieu-Nosjean, Marie-Caroline, ed. Tertiary Lymphoid Structures. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2.

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Dieu-Nosjean, Marie-Caroline, ed. Tertiary Lymphoid Structures. New York, NY: Springer US, 2025. http://dx.doi.org/10.1007/978-1-0716-4184-2.

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Dieu-Nosjean, Marie-Caroline. Tertiary Lymphoid Structures: Methods and Protocols. Springer New York, 2018.

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Dieu-Nosjean, Marie-Caroline. Tertiary Lymphoid Structures: Methods and Protocols. Springer New York, 2019.

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Verma, Vivek, Catherine Sautes-Fridman, and Anna Dimberg, eds. Tertiary Lymphoid Structures: from Basic Biology to Translational Impact in Cancer. Frontiers Media SA, 2022. http://dx.doi.org/10.3389/978-2-88974-862-4.

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Book chapters on the topic "Tertiary lymphoid structure"

1

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, and 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, and 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, and 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, and 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., and 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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Silva-Sanchez, Aaron, Troy D. Randall, and Selene Meza-Perez. "Tertiary Lymphoid Structures Among the World of Noncanonical Ectopic Lymphoid Organizations." In Tertiary Lymphoid Structures, 1–15. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_1.

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Corsiero, Elisa, Lucas Jagemann, Michele Bombardieri, and Costantino Pitzalis. "Generation of Recombinant Monoclonal Antibodies from Single B Cells Isolated from Synovial Tissue of Rheumatoid Arthritis Patients." In Tertiary Lymphoid Structures, 159–87. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_10.

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Teillaud, Jean-Luc, Lucile Regard, Clémence Martin, Sophie Sibéril, and Pierre-Régis Burgel. "Exploring the Role of Tertiary Lymphoid Structures Using a Mouse Model of Bacteria-Infected Lungs." In Tertiary Lymphoid Structures, 223–39. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_13.

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Rodriguez, Anthony B., J. David Peske, and Victor H. Engelhard. "Identification and Characterization of Tertiary Lymphoid Structures in Murine Melanoma." In Tertiary Lymphoid Structures, 241–57. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8709-2_14.

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Conference papers on the topic "Tertiary lymphoid structure"

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Li, Rong, Rui Chen, Jingwen Yue, Le Liu, and Zijian Jia. "Segmentation and Quantitative Evaluation of Tertiary Lymphoid Structures in Hepatocellular Carcinoma Based on Deep Learning." In 2024 2nd International Conference on Algorithm, Image Processing and Machine Vision (AIPMV), 31–35. IEEE, 2024. http://dx.doi.org/10.1109/aipmv62663.2024.10692225.

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Yang, Yang, Mei Xie, Yimiao Feng, Xueheng Lv, Jialin Song, Xinying Xue, and Jie Zheng. "CellSeg2TLS: A Deep Learning Framework for Predicting the Maturation of Tertiary Lymphoid Structures in Pathology Images." In 2024 IEEE International Symposium on Biomedical Imaging (ISBI), 1–5. IEEE, 2024. http://dx.doi.org/10.1109/isbi56570.2024.10635596.

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Karapetyan, Lilit, Xi Yang, Hong Wang, Cindy Sander, Arivarasan Karunamurthy, John M. Kirkwood, and 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, and 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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Koedijk, J. B., I. van der Werf, M. A. Vermeulen, A. Perzolli, M. Fiocco, H. A. de Groot-Kruseman, S. Nierkens, M. E. Belderbos, C. M. Zwaan, and O. Heidenreich. "Spatial analysis reveals distinct immune phenotypes and tertiary lymphoid structure-like aggregates in pediatric AML." In 34. Jahrestagung der Kind-Philipp-Stiftung für pädiatrisch onkologische Forschung. Georg Thieme Verlag, 2023. http://dx.doi.org/10.1055/s-0043-1768524.

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Wolfgang, Katelyn, Jessica A. Jana, Kristin Morder, Dipyaman Patra, Kelsey Ertwine, and Abigail E. Overacre-Delgoffe. "1264 Investigating the mechanisms ofHelicobacter hepaticusmediated lymphangiogenesis and tertiary lymphoid structure formation." In SITC 39th Annual Meeting (SITC 2024) Abstracts, A1420. BMJ Publishing Group Ltd, 2024. http://dx.doi.org/10.1136/jitc-2024-sitc2024.1264.

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Arora, Charu, Renee R. Anderko, Noor Nader, Sheryl Kunning, Amer Zureikat, and Tullia C. Bruno. "1367 Autophagy inhibition in pancreatic ductal adenocarcinoma cancer patients modulates tertiary lymphoid structure activity and B cell function." In SITC 39th Annual Meeting (SITC 2024) Abstracts, A1531. BMJ Publishing Group Ltd, 2024. http://dx.doi.org/10.1136/jitc-2024-sitc2024.1367.

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Wang, Xuefeng, Ranran Tao, Tingyi Li, Sandra J. Lee, Islam Eljilany, Howard Streicher, Walter J. Storkus, Arivarasan D. Karunamurthy, John M. Kirkwood, and Ahmad A. Tarhini. "137 Tertiary lymphoid structure signature in digital H&E slides as a prognostic biomarker in cutaneous melanoma." In SITC 39th Annual Meeting (SITC 2024) Abstracts, A153. BMJ Publishing Group Ltd, 2024. http://dx.doi.org/10.1136/jitc-2024-sitc2024.0137.

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Pimenta, Erica, Ryan Weiss, Dan Li, and Betsy Barnes. "Abstract 4141: Role of interferon regulatory factor 5 in anti-tumor immunity: Orchestration of a functional tertiary lymphoid structure." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4141.

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Ruiyi, Xu, and Wang Hui. "EP084/#264 The landscape of immune microenvironment and the poor prognostic value of tertiary lymphoid structure in gastric-type mucinous carcinoma." In IGCS 2023 Annual Meeting Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/ijgc-2023-igcs.188.

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Reports on the topic "Tertiary lymphoid structure"

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Lin, Liying, Min Li, Bo Fu, Miaomiao Chu, Song Wang, Bingwu Yang, and 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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