Thematische Bibliographien / Structure lymphoide tertiaire (TLS)

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Auswahl der wissenschaftlichen Literatur zum Thema „Structure lymphoide tertiaire (TLS)“

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Veröffentlicht am 23. November 2024

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Zeitschriftenartikel zum Thema "Structure lymphoide tertiaire (TLS)"

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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Cai, Daming, Heng Yu, Xingzhou Wang, Yonghuan Mao, Mengjie Liang, Xiaofeng Lu, Xiaofei Shen und Wenxian Guan. „Turning Tertiary Lymphoid Structures (TLS) into Hot Spots: Values of TLS in Gastrointestinal Tumors“. Cancers 15, Nr. 2 (05.01.2023): 367. http://dx.doi.org/10.3390/cancers15020367.

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Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregation structures found in the tumor microenvironment (TME). Emerging evidence shows that TLSs are significantly correlated with the progression of gastrointestinal tumors, patients’ prognosis, and the efficacy of adjuvant therapy. Besides, there are still some immunosuppressive factors in the TLSs that may affect the anti-tumor responses of TLSs, including negative regulators of anti-tumor immune responses, the immune checkpoint molecules, and inappropriate tumor metabolism. Therefore, a more comprehensive understanding of TLSs’ responses in gastrointestinal tumors is essential to fully understand how TLSs can fully exert their anti-tumor responses. In addition, targeting TLSs with immune checkpoint inhibitors and vaccines to establish mature TLSs is currently being developed to reprogram the TME, further benefiting cancer immunotherapies. This review summarizes recent findings on the formation of TLSs, the mechanisms of their anti-tumor immune responses, and the association between therapeutic strategies and TLSs, providing a novel perspective on tumor-associated TLSs in gastrointestinal tumors.

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Vaghjiani, Raj G., und Joseph J. Skitzki. „Tertiary Lymphoid Structures as Mediators of Immunotherapy Response“. Cancers 14, Nr. 15 (01.08.2022): 3748. http://dx.doi.org/10.3390/cancers14153748.

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Since its first application in the treatment of cancer during the 1800s, immunotherapy has more recently become the leading edge of novel treatment strategies. Even though the efficacy of these agents can at times be predicted by more traditional metrics and biomarkers, often patient responses are variable. TLS are distinct immunologic structures that have been identified on pathologic review of various malignancies and are emerging as important determinants of patient outcome. Their presence, location, composition, and maturity are critically important in a host’s response to malignancy. Because of their unique immunogenic niche, they are also prime candidates, not only to predict and measure the efficacy of immunotherapy agents, but also to be potentially inducible gatekeepers to increase therapeutic efficacy. Herein, we review the mechanistic underpinnings of TLS formation, the data on its relationship to various malignancies, and the emerging evidence for the role of TLS in immunotherapy function.

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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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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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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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Berthe, Julie, Sriram Sridhar, Felix Segerer, Marco Testori, Megha Saraiya, Lorenz Rognoni, Harald Hessel et al. „39 A multi-modal analysis approach leveraging multiplexed spatial phenotyping and multi-omics analysis to better understand the prognostic value of tertiary lymphoid structures in NSCLC“. Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A46. http://dx.doi.org/10.1136/jitc-2021-sitc2021.039.

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BackgroundTertiary Lymphoid Structures (TLS) are highly organized ectopic lymphoid structures found in inflamed or tumor tissues, acting as sites of lymphoid recruitment and immune activation. A high TLS density within the tumor is commonly associated with an increased prognostic effect of TILs and with an improved disease free survival and overall survival for patients.1 However, the existence of conflicting studies suggest that multiple TLS features should be taken into account when assessing their prognostic value, such as their location, cellular composition, maturation stage and spatial organisation, as those may affect their functionalities.2MethodsWith the aim of gaining insights into TLS biology and evaluating the prognostic role of TLS in Non-Small Cell Lung Carcinoma according to their multiple features, we developed a TLS multiplex immunofluorescent (mIF) panel that includes T cells (CD3, CD8), B cells (CD20), Follicular Dendritic cells (CD21, CD23) and mature dendritic cells (DC-LAMP) markers. We deployed this panel across a cohort of primary tumors from NSCLC patients (n=408) and established a mIF image analysis workstream to assess the status and spatial location of each cell within the tissue. A H&E staining of the same tissue section was performed to evaluate mIF spatial data in relation to the tumor context. Additional multi-omics assessments were conducted across the same cohort including; whole exome sequencing, NanoString transcriptomics, and immunohistochemistry (e.g. PD-L1, FOXP3, NKp46, LKB1, CTLA4). We have leveraged clinical metadata, including demographics (e.g. age, sex, smoking status) and clinical risk factors (e.g. stage, grade, Standard of Care treatment) with clinical follow up (e.g. OS, PFS) for prevalence analysis, novel biomarker identification, and survival association.ResultsAssessment of the prevalence of each cell phenotype within the tumor tissue and TLS, the cell-cell interactions, the distance between each cell type, and the distance of non-TLS immune cells to the closest TLS will be described, demonstrating the different types of lymphoid aggregates and TLS and their functional status. An integrative analysis combining spatial biology data with multi-omics and clinical data will be presented evaluating the prognostic value of TLS composition, maturation status and spatial organization, in correlation with additional biomarkers and clinical characteristics.ConclusionsThis exploratory study using cutting-edge technologies enables us to better understand how TLS orchestrate an organised anti-tumour response, defining TLS spatial biomarker signatures, TLS gene signatures, and TLS features associated with patient outcomes to evaluate in the clinic.ReferencesMarie-Caroline Dieu-Nosjean, Jérémy Goc, Nicolas A Giraldo, Catherine Sautès-Fridman, Wolf Herman Fridman. Tertiary lymphoid structures in cancer and beyond. Trends Immunol 2014;35(11):571–580.Catherine Sautès-Fridman, Florent Petitprez, Julien Calderaro, Wolf Herman Fridman. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 2019;19(6):307–325.Ethics ApprovalThe study was approved by AstraZeneca.

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Trajkovski, Gjorgji, Ljubomir Ognjenovic, Zoran Karadzov, Gjorgji Jota, Dragan Hadzi-Manchev, Ognen Kostovski, Goce Volcevski et al. „Tertiary Lymphoid Structures in Colorectal Cancers and Their Prognostic Value“. Open Access Macedonian Journal of Medical Sciences 6, Nr. 10 (09.10.2018): 1824–28. http://dx.doi.org/10.3889/oamjms.2018.341.

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Abstract Introduction: Tumor-infiltrating lymphocytes (TIL) in tumor stroma are considered to be involved in elimination of malignant cells and in prevention of metastasis formation. TIL are consisted of T lymphocytes including cytotoxic lymphocytes that are a constituent part of the effector mechanism of anti-tumor immunity and B lymphocytes that can form tertiary lymphoid structures (TLS). TLS have been described in several solid tumors and in colorectal carcinoma (CRC) and they influence on the local and systemic anti-cancer response. The aim of this study was to quantify the presence of TLS in CRC patients and to determine their role in tumor progression. Patients and methods: The study included 103 patients with CRC who underwent surgery at the University Clinic of Digestive Surgery in Skopje, whose operative material was analyzed at the Institute of Pathology, Medical Faculty in Skopje. The density of TLS was determined and correlated with neoplasm status of local growth (T), positive lymph nodes, lymphatic invasion, stage of the disease and tumor grade. Results: The density of TLS was significantly higher in patients with higher stage, lower T status, negative lymph nodes, in patients with no lymphatic invasion and with better differentiated tumors. Conclusion: The density of TLS plays an important role in controlling the tumor growth and it can be a parameter for neoplasm progression in CRC patients. The density of TLS has influence on the control of tumor progression.

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Filderman, Jessica, und Walter Storkus. „Therapeutic vascular normalization to promote tumor-associated tertiary lymphoid structures“. Journal of Immunology 204, Nr. 1_Supplement (01.05.2020): 89.6. http://dx.doi.org/10.4049/jimmunol.204.supp.89.6.

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Abstract Tertiary lymphoid structures (TLS) are non-encapsulated immune cell aggregates that form at sites of chronic inflammation. Recent studies have shown that the presence of TLS in human tumors indicates positive clinical outcome. However, many tumors have poorly organized and leaky vasculature that impedes entry of immune effector cells into tumors and consequently TLS formation. Recently, studies have shown that low doses of antiangiogenic agents normalize tumor vasculature, leading us to hypothesize that treating tumors with low doses of vascular normalizing (VN) therapies will improve immune cell infiltration and TLS formation within the tumor microenvironment (TME). To test this hypothesis, tumor-bearing mice were treated intratumorally with VN agents. RNA was isolated from digested tumors and transcript levels of TLS-promoting factors and markers of inflammation/immune cell infiltration were measured and compared to PBS treated controls. Changes in tumor vasculature were evaluated using immunofluorescence microscopy. Additionally, primary cultures of murine T cells and DCs and the BPR melanoma cell line were treated in vitro with VN agents. We observed that the VN agents dasatinib, STING agonist, bevacizumab, and agonist anti-TNFR1 antibody each induced global changes in the TME that are potentially supportive of immune cell infiltration and TLS formation. In vitro, dasatinib induced DCs and BPR melanoma cells to express higher levels of co-stimulatory receptors, MHC class I and II, and TLS-promoting chemokines. Treatment with a STING agonist was able to enhance T cell activation, while treatment with dasatinib inhibited T cell activation.

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Kushnarev, Vladimir, Daniil Dymov, Nadezhda Lukashevich, Lev Popyvanov, Anna Belozerova, Diana Shamsutdinova, Aida Akaeva et al. „Abstract P6-04-15: AI-based prediction of tertiary lymphoid structures and lymphocyte immune infiltration in breast carcinomas“. Cancer Research 83, Nr. 5_Supplement (01.03.2023): P6–04–15—P6–04–15. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-04-15.

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Abstract Introduction Tertiary lymphoid structures (TLSs) and tumor-infiltrating lymphocytes (TILs) in breast carcinomas are prognostic for survival and predictive of certain therapy responses. The presence of TLSs and TILs are identified by manual pathological examination; however, this method often lacks reproducibility, limiting its use in routine clinical practice. Here, we demonstrate that morphological evaluation of whole slide images (WSIs) using an artificial intelligence (AI)-based analytic workflow comprised of convolutional neural network (CNN) deep learning models that accurately and reproducibly characterizes TILs, measured as the lymphocyte immune-infiltrated area (LIIA), and TLSs in the tumor microenvironment (TME) of breast carcinomas. Methods We collected a cohort of 445 TCGA breast cancer H&E WSIs, including clinical and sequencing data, and divided this cohort into luminal invasive lobular carcinoma (ILC) (n = 192), HER2-enriched (n = 110), and basal-like (n = 143) molecular subtypes. After 55 samples were excluded due to artifacts or incomplete clinical annotation, a total of 390 samples were analyzed. A combination of CNN-based deep learning models was used to detect and classify the tumor area, TLSs present in the TME, TLS density (number of TLS per mm2 of tumor), and lymphocyte-rich regions. The LIIA was calculated as the area of the stromal and TIL components of the TME. Validation was performed by manually annotating 10 random WSIs from the dataset. Spatial model predictions of the tumor and TLSs were combined to identify TLS locations. Each model’s predictions were verified by univariate (Kaplan-Meier) and multivariate (Cox regression) survival analyses, and the log-rank test was used to calculate overall survival. Additionally, the relationship between TLSs and LIIAs with CD274 expression (PD-L1) and a high tumor mutational burden (TMB > 10) was analyzed. Statistical analyses included Spearman’s rank correlation and Mann-Whitney tests. Results TLS were detected in 53% (n = 207) of the samples, with a mean density of 26.02 TLS/mm2 (Q3 = 5.53 TLS/mm2). TLS density was higher in basal-like subtype samples compared to luminal and HER2-enriched subtypes. While LIIA and TMB-high samples exhibited a significant relationship (p = 0.00001), no significant association was found between TME and TLS quantities or density. PD-L1 gene expression exhibited weak to moderate correlations with predicted LIIA in basal-like (r = 0.38, p = 0.00001) and HER2-enriched subtypes (r = 0.38, p = 0.0001). The luminal subtype had no significant correlation between PD-L1 expression and predicted LIIA. As a result, LIIA and TLS were characterized as positive prognostic factors for the basal-like subtype. After adjusting for age, stage, and grade, the LIIA and TLS density were found to be significant independent positive prognostic overall survival factors for the basal-like subtype (LIIA HR: 0.02, p = 0.003; TLS-high group HR: 0.09, p = 0.002). For the HER2-enriched subtype, TLS density was also a significant predictor (HR: 0.05, p = 0.035), while LIIA was not a statistically significant prognostic factor (HR: 0.0002, p = 0.08). Associations were not observed between the TLSs and LIIA between the ILC subtypes and survival outcomes. The same result was observed for univariate analyses. Conclusion The developed analytic pipeline accurately identified the presence of LIIA and TLS on H&E slides, demonstrating the potential of CNN for automated characterization of the breast cancer TME. AI-based TLS and LIIA quantification can be a robust tool for pathology processes, offering additional information to help in clinical decision-making. This approach can be used to detect features of immune morphology biomarkers in other cancer types. Citation Format: Vladimir Kushnarev, Daniil Dymov, Nadezhda Lukashevich, Lev Popyvanov, Anna Belozerova, Diana Shamsutdinova, Aida Akaeva, Yury Popov, Svetlana Khorkova, Ivan Valiev, Anastasia Zotova, Jessica H. Brown, Anna Love, Alexander Bagaev, Ekaterina Postovalova, Nathan Fowler. AI-based prediction of tertiary lymphoid structures and lymphocyte immune infiltration in breast carcinomas [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-04-15.

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Dissertationen zum Thema "Structure lymphoide tertiaire (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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Buchteile zum Thema "Structure lymphoide tertiaire (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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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 "Structure lymphoide tertiaire (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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