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1
Zou, Ji’an, Yingzhe Zhang, Yue Zeng, Yurong Peng, Junqi Liu, Chaoyue Xiao, and Fang Wu. "Tertiary Lymphoid Structures: A Potential Biomarker for Anti-Cancer Therapy." Cancers 14, no. 23 (December 2, 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, and Wenxian Guan. "Turning Tertiary Lymphoid Structures (TLS) into Hot Spots: Values of TLS in Gastrointestinal Tumors." Cancers 15, no. 2 (January 5, 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., and Joseph J. Skitzki. "Tertiary Lymphoid Structures as Mediators of Immunotherapy Response." Cancers 14, no. 15 (August 1, 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, and Yang Xia. "Decreased Tertiary Lymphoid Structures in Lung Adenocarcinomas with ALK Rearrangements." Journal of Clinical Medicine 11, no. 19 (October 8, 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 (October 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, 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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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, no. 10 (October 9, 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, and Walter Storkus. "Therapeutic vascular normalization to promote tumor-associated tertiary lymphoid structures." Journal of Immunology 204, no. 1_Supplement (May 1, 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, no. 5_Supplement (March 1, 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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Sofronii, Doïna, Francine Padonou, Mireille Langouo, Noemie Thomas, Anais Boisson, Alexandre De Wind, Denis Larsimont, Ahmad Awada, Soizic Garaud, and Karen Willard-Gallo. "Abstract 4618: Biomarkers of functionally active tertiary lymphoid structures in human breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4618. http://dx.doi.org/10.1158/1538-7445.am2023-4618.
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Abstract The clinical relevance of tumor infiltrating lymphocytes (TIL) in breast cancer (BC) is now widely accepted and being implemented in clinical practice. Our lab previously demonstrated that 60% of BC organize some of their TIL in tertiary lymphoid structures (TLS). TLS have been detected in a wide variety of solid tumors with their prognostic value and importance in the response to immunotherapy increasingly accepted. Reliable biomarkers to identify and characterize TLS and their immune activities in tumors are needed. The specific aim of this project was to perform a comprehensive analysis across the spectrum of TLS states to identify biomarkers associated with active and inactive TLS, where the former are associated with functional anti-tumor immunity and improved responses to treatment and long-term survival. This study analyzed FFPE tissues from 38 primary untreated HER2+ and triple negative (TN) BC patients. Patients were divided into two groups based on a TLS score evaluating CD3/CD20 and PD-1/Ki-67 dual IHC-stained tumor tissues: 1) BC containing a majority of active TLS (tumors with only active TLS have never been observed), defined by the presence of a germinal center (GCpos ; Ki-67+ follicular B cells) and 2) BC with only inactive TLS (GCneg ; Ki-67− follicular B cells). Controls included normal breast tissues, BC without TLS and lymphoid tissues (reactive tonsils for GCpos and spleens for GCneg TLS). RNA extracts from microdissected tissues (N=100), including active TLS, inactive TLS and lymphoid B follicles, were sequenced. DESeq2 and CIBERSORT were employed to quantify differentially expressed genes and immune cell subpopulations, respectively. Gene Set Enrichment Analysis was used for additional data interpretation and pathway identification. Tumors from patients with active TLS were characterized by increased naïve and plasma B cell TIL compared to tumors with only inactive TLS. Preliminary analysis of the differentially expressed genes in active TLS (vs inactive TLS) revealed upregulation of key B cell differentiation, somatic hypermutation and class switch recombination genes, which paralleled their respective lymphoid controls. These gene upregulations were linked with a GC presence in active TLS. A specific set of immunoglobulin genes were also differentially expressed in active TLS. Continued analysis of the TLS data, including their cellular composition, location, maturation and functionality, along with data confirmation (RT-PCR and multiplex IHC), and assessment of their functional and clinical relevance is ongoing. Our preliminary results suggest that active B cell differentiation and Ig production contribute to TLS functionality. In lymphoid tissues, the GC plays important roles in orchestrating the molecular and cellular programs of humoral immunity. Our data suggest that active GC-containing TLS foster an immune microenvironment in BC that favors positive clinical outcomes. Citation Format: Doïna Sofronii, Francine Padonou, Mireille Langouo, Noemie Thomas, Anais Boisson, Alexandre De Wind, Denis Larsimont, Ahmad Awada, Soizic Garaud, Karen Willard-Gallo. Biomarkers of functionally active tertiary lymphoid structures in human breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4618.
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Li, Jianhui, Ye Nie, Weili Jia, Wenlong Wu, Wenjie Song, and Yongxiang Li. "Effect of Tertiary Lymphoid Structures on Prognosis of Patients with Hepatocellular Carcinoma and Preliminary Exploration of Its Formation Mechanism." Cancers 14, no. 20 (October 21, 2022): 5157. http://dx.doi.org/10.3390/cancers14205157.
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Background: Tertiary lymphoid structures (TLSs) are formed by the aggregation of tumour-infiltrating lymphocytes (TILs), which is driven by chemokines or cytokines in the tumour microenvironment. Studies have shown that TLSs are associated with good prognosis in patients with various solid tumours and can improve patient responses to immunotherapy. However, the role of TLSs in hepatocellular carcinoma (HCC) remains controversial, and the underlying molecular mechanism is unclear. Methods: According to haematoxylin-eosin (HE) staining results, HCC patients in Xijing Hospital data and TCGA data were divided into TLS+ and TLS- groups, and Kaplan–Meier (KM) analysis was performed to assess overall survival (OS) and recurrence-free survival (RFS). Immunofluorescence (IF) and immunohistochemistry (IHC) were used to identify TILs in the TLS+ group. Lymphocyte-specific protein tyrosine kinase (LCK), a molecule involved in TLS formation, was explored in LinkedOmics. TILs were divided into two groups by drawing receiver operating characteristic (ROC) curves to calculate cut-off values. Spearman correlation analysis was used to calculate the correlation between LCK and TILs, and the molecular pathways by which LCK regulates immunotherapy were clarified through enrichment analysis. The half-maximal inhibitory concentration (IC50) distribution of sorafenib was observed in groups that varied in LCK expression. Results: According to the HE results, 61 cases in the Xijing Hospital cohort and 195 cases in the TCGA cohort had TLSs, while 89 cases and 136 cases did not. The KM results showed that TLSs had no effect on the OS of HCC patients but significantly affected RFS. The IF/IHC results showed that higher TIL numbers in TLSs were correlated with better prognosis in HCC patients. Spearman correlation analysis showed that LCK expression was positively correlated with TIL numbers. Enrichment analysis showed that upregulation of LCK expression mainly regulated the cytokine signalling pathway, the chemokine signalling pathway and T-cell activation. The IC50 scores of sorafenib in HCC patients with high LCK expression were lower, and the sensitivity was higher. Conclusion: TLSs mainly affected the early RFS of HCC patients but had no effect on OS. The high expression of the TLS formation-related gene LCK can increase the sensitivity of HCC patients to ICIs.
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Yu, Jinglu, Yabin Gong, Xiaowei Huang, and Yufang Bao. "Prognostic and therapeutic potential of gene profiles related to tertiary lymphoid structures in colorectal cancer." PeerJ 12 (October 31, 2024): e18401. http://dx.doi.org/10.7717/peerj.18401.
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The role of tertiary lymphoid structures (TLS) in oncology is gaining interest, particularly in colorectal carcinoma, yet a thorough analysis remains elusive. This study pioneered a novel TLS quantification system for prognostic and therapeutic response prediction in colorectal carcinoma, alongside a comprehensive depiction of the TLS landscape. Utilizing single-cell sequencing, we established a TLS score within the Tumor Immune Microenvironment (TIME). Analysis of tertiary lymphoid structure-related genes (TLSRGs) in 1,184 patients with colon adenocarcinoma/rectum adenocarcinoma (COADREAD) from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases led to the identification of two distinct molecular subtypes. Differentially expressed genes (DEGs) further segregated these patients into gene subtypes. A TLS score was formulated using gene set variation analysis (GSVA) and its efficacy in predicting immunotherapy outcomes was validated in two independent cohorts. High-scoring patients exhibited a ‘hot’ immune phenotype, correlating with enhanced immunotherapy efficacy. Key genes in our model, including C5AR1, APOE, CYR1P1, and SPP1, were implicated in COADREAD cell proliferation, invasion, and PD-L1 expression. These insights offer a novel approach to colorectal carcinoma treatment, emphasizing TLS targeting as a potential anti-tumor strategy.
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Chelvanambi, Manoj, Jennifer L. Taylor, Ronald J. Fecek, and Walter J. Storkus. "Therapeutic Induction of Tertiary Lymphoid Structures in Melanoma using STING Agonists." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 194.27. http://dx.doi.org/10.4049/jimmunol.202.supp.194.27.
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Abstract Tertiary lymphoid structures (TLS) are non-encapsulated functional aggregates of T cells, B cells, dendritic cells (DC) and high endothelial venules (HEV) located in peripheral sites of chronic inflammation. TLS may serve as sites of local antigen presentation and immune priming that may protect against tumor progression. Homeostatic chemokines CCL19, CCL21 and CXCL13 produced by DCs and/or stromal cells are known to support secondary lymphoid organogenesis and also play key roles in TLS formation. Other DC-associated pro-inflammatory cytokines including lymphotoxin α, IL-36γ and type I interferons also appear to aid in organizing TLS. Hence, we hypothesize that appropriate therapeutic activation of DCs within the tumor microenvironment may serve to nucleate TLS in vivo, leading to slowed tumor progression. We found that activation of the cytosolic DNA sensor STING using ML-RR-S2-CDA, a murine and human STING agonist, leads to not only an expected increased production of type I interferons by CD11c+ DCs in vitro but also leads to increased transcript levels of TLS-associated cytokines/chemokines via activation of pIRF3 and pIRF7. In mice harboring B16.F10 melanomas, provision of STING agonists slows tumor growth in a host STING dependent manner. Further using immunofluorescence microscopy, we observed increased infiltration and clustering of CD3+ T cells and CD11c+ DCs and the induction of HEVs in treated tumors within tumor-associated TLS as early as 5 days post-treatment. Future studies will determine how TLS shape the local versus systemic protective T cell repertoire in treated animals.
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Krull, Jordan, Anjali Byappanahalli, Yi Jiang, Andrew Gunderson, and Qin Ma. "Abstract 4879: Delineating lymphocyte aggregates from tertiary lymphoid structures using spatial transcriptomics." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4879. http://dx.doi.org/10.1158/1538-7445.am2024-4879.
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Abstract Tertiary Lymphoid Structures (TLSs) are ectopic lymphoid structures that form in chronically inflamed non-lymphoid tissue. The presence of TLSs in tumors is largely associated with favorable outcomes among patients and also exhibit positive associations with response to immune checkpoint blockade. Although mainly comprised of lymphocytes (B cells and T cells), they are considered a separate entity from lymphocyte aggregates within tissue. Lymphocyte aggregates are fairly routine to identify in H&E stained tissue sections, but delineating TLSs from simple lymphocyte aggregates is subjective and not clearly defined. Additionally, the definition of TLSs is only recently being elucidated, so a clear molecular definition of both TLSs and lymphocyte aggregates is needed. To address this problem, we leveraged open-source spatial transcriptomics (ST) data from 17 samples across 7 cancer types. High resolution H&E images were manually evaluated for lymphocyte aggregates by identifying dense pockets of lymphocytic-appearing nuclei. Suspected aggregates were detected in 10 of 17 samples. We then applied a visium spot-level signature scoring method for 4 well published TLS signatures. Of the spots identified, 62% had enhanced signature expression for at least 2 of the signatures, although most of the incorrect annotations came from the lone gastric cancer sample. Differential expression between a TLS-sig- suspected lymphoid aggregate and a TLS-sig+ region not identified by H&E enriched primarily for B cell identity genes, suggesting B-cell-rich TLSs may not always appear as lymphoid aggregates in histology. [AG1] Strikingly, ST revealed strongly positive enhancements in the TLS signatures, where no annotations were made, and no obvious lymphoid aggregation was present, suggesting manual annotation from H&E is inadequate for identifying TLSs. Together, these results demonstrate that literature derived TLS signatures can correctly identify lymphoid aggregates as TLSs and that cellular and molecular differences between standard lymphoid aggregates and TLSs may be smaller than is currently accepted. Citation Format: Jordan Krull, Anjali Byappanahalli, Yi Jiang, Andrew Gunderson, Qin Ma. Delineating lymphocyte aggregates from tertiary lymphoid structures using spatial transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4879.
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Filderman, Jessica, Manoj Chelvanambi, and Walter Storkus. "584 Therapeutic vascular normalization to promote tumor-associated tertiary lymphoid structures." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A619. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0584.
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BackgroundTertiary lymphoid structures (TLS) are non-encapsulated immune cell aggregates that form at sites of chronic inflammation, including in and around tumors. Recent studies have shown that the presence of TLS in human tumors is an indicator of positive clinical outcome. However, due to dysregulated angiogenesis, many tumors have a poorly-organized and leaky vasculature that impedes entry of immune effector cells into tumors and consequently, TLS formation. It has been shown in pre-clinical studies that low doses of antiangiogenic agents normalize the tumor vasculature, leading us to hypothesize that treating tumors with low-doses (well below drug MTD) of vascular normalizing (VN) therapies will improve immune cell infiltration and TLS formation within the tumor microenvironment (TME).MethodsTo test this hypothesis, melanoma-bearing mice were treated intratumorally with VN agents. Five days post-treatment, tumors were digested into single cell suspensions and RNA was isolated and used for RT-PCR. Transcript levels of TLS-promoting factors (CCL19, CCL21, CXCL13) and markers of vascular normalization (HIF1A, GLUT1) and inflammation/immune cell infiltration (CXCL10, VCAM1, CD8A) were measured and compared to PBS treated controls. Changes in tumor vasculature were evaluated using immunofluorescence microscopy (IFM) of tumor sections stained with CD31, PNAd, and PDGFRβ. Fluorescently-labeled lectin was injected into the mice to observe tumor perfusion. TLS formation was evaluated in tumor sections using IFM, with TLS being defined as PNAd+ vessels surrounded by clusters of CD45+ cells.ResultsWe observed that the VN agents dasatinib, STING agonist, bevacizumab, and agonist anti-TNFR1 antibody each induced global changes in the TME that are consistent with enhanced immune cell infiltration and TLS formation. These changes include increases in expression of CCL19, CCL21, and VCAM1. Dasatinib and STING agonists were shown to promote VN, as demonstrated by improved lectin perfusion into the tumor and increased pericyte coverage of blood vessels on-treatment.ConclusionsVN agents induce global changes in immune cell infiltration and TLS-promoting factors in the TME. In vivo, these agents induce VN in the TME and promote TLS formation. This knowledge can be used to develop optimal combination immunotherapy designs in the cancer setting.
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Zeng, Zheng, Yee Man Au-Yeung, and Jiandong Huang. "Abstract 7466: Exploring tertiary lymphoid structures and immune cell interactions in gastric cancer prognosis." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7466. http://dx.doi.org/10.1158/1538-7445.am2024-7466.
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Abstract Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in chronically inflamed, infected, and tumor tissues. Prior research indicates that the presence of TLS and tumor-infiltrating lymphocytes (TILs) correlates with a more favorable prognosis in several cancers. Our study investigates the role of TLSs and TILs in gastric cancer, the 4th leading cause of cancer-related death worldwide. We analyzed tumor samples from 107 late-stage gastric cancer patients from mainland China, with a 5-year follow-up period. We performed H&E and multiplex immunofluorescence staining to assess the tumor area and infiltrating immune cells, and we evaluated potential relationships between TILs, clinicopathological features, and patient prognosis. Immunohistological analysis showed that CD4 T cells may have a more significant impact on patient prognosis than CD8 T cells. Notably, the presence of PDL1 and CD4 co-expressing cells was associated with better disease outcomes. We observed PDL1 expressing cells surrounding the tumor margin in a subset of cases, a distribution pattern that could lead to delayed recurrence or complete remission in gastric cancer. In the context of cancer-related TLS, we found that CD20 and CD86 co-expression in the center of the structures may indicate a higher maturation level. Additionally, the ratio and spatial distribution of CD86 and CD163 macrophages appear to play a crucial role in prognosis. We extracted the expression levels of markers from representative samples to examine the spatial relationships between cancer cells and each immune cell type. We then visualized these cellular interactions in the tumor microenvironment using topographic plots. This study broadens our understanding of tumor and immune cell interactions in gastric cancer, with the potential to inform future directions in immunotherapy treatments. Citation Format: Zheng Zeng, Yee Man Au-Yeung, Jiandong Huang. Exploring tertiary lymphoid structures and immune cell interactions in gastric cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7466.
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Narvaez, Dana, Jorge Nadal, Adrian Nervo, María Victoria Costanzo, Claudio Paletta, Fernando E. Petracci, Sergio Rivero, et al. "The Emerging Role of Tertiary Lymphoid Structures in Breast Cancer: A Narrative Review." Cancers 16, no. 2 (January 17, 2024): 396. http://dx.doi.org/10.3390/cancers16020396.
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This narrative review aims to clarify the role of tertiary lymphoid structures in breast cancer. We examine their development, composition, and prognostic value, and current ways of recognizing them. A comprehensive literature review was performed using the PubMed/Medline, Scopus, and EMBASE databases. A significant area of interest in breast cancer research involves targeting immune checkpoint molecules, particularly in the triple-negative subtype, where treatment options remain limited. However, existing biomarkers have limitations in accurately predicting treatment response. In this context, tertiary lymphoid structures (TLSs) emerge as a prognostic biomarker and also as a promising predictive marker for response. TLSs are ectopic lymphoid formations or neo-organogenesis that can develop after prolonged exposure to inflammatory signals mediated by chemokines and cytokines. Their presence is inversely correlated with estrogen receptor (ER) and/or progesterone receptor (PR) expression, but positively associated with a higher pathologic complete response rate and improved overall survival. In certain scenarios, TLS-positive tumors were associated with improved outcomes regardless of the presence of PDL-1 (programmed cell death ligand 1) expression or TILs (tumor-infiltrating lymphocytes).
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Nayar, Saba, Joana Campos, Charlotte G. Smith, Valentina Iannizzotto, David H. Gardner, Frédéric Mourcin, David Roulois, et al. "Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology." Proceedings of the National Academy of Sciences 116, no. 27 (June 18, 2019): 13490–97. http://dx.doi.org/10.1073/pnas.1905301116.
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Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.
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Lynch, Kevin T., Samuel J. Young, Max O. Meneveau, Nolan A. Wages, Victor H. Engelhard, Craig L. Slingluff Jr, and Ileana S. Mauldin. "Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma." Journal for ImmunoTherapy of Cancer 9, no. 6 (June 2021): e002273. http://dx.doi.org/10.1136/jitc-2020-002273.
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BackgroundTertiary lymphoid structures (TLSs) are immune aggregates in peripheral tissues that may support adaptive immune responses. Their presence has been associated with clinical response to checkpoint blockade therapy (CBT), but it is unknown whether TLS have prognostic significance independent of CBT in melanoma. We hypothesized that TLS in melanoma metastases would be associated with increased intratumoral lymphocyte infiltration, but that the intra-TLS immunological milieu would be distinct from the intratumoral immunological milieu. We also hypothesized that the presence of TLS would be associated with improved survival, and that TLS maturation or intra-TLS lymphocyte activity would also correlate with survival.MethodsCutaneous melanoma metastases (CMM) from 64 patients were evaluated by multiplex immunofluorescence for the presence and maturation status of TLS. Intra-TLS lymphocyte density, proliferation and B-cell Ig somatic hypermutation (AID+) were analyzed, as were markers of T-cell exhaustion and Th1/Tc1 differentiation. Associations between TLS maturation and intra-TLS immunologic activity were assessed, as well as associations with intratumoral immune cell infiltration. Independent associations with overall survival (OS) were assessed using log-rank tests and Cox proportional hazards models.ResultsTLS were identified in 30 (47%) of 64 CMM (TLS+) and were associated with increased intratumoral lymphocyte infiltration. However, proliferation of intra-TLS lymphocytes did not correlate with intratumoral lymphocyte proliferation. Most were early TLS; however, subsets of primary or secondary follicle-like TLS were also present. TLS+ lesions were associated with lower risk of tumor recurrence after metastasectomy and with improved OS in multivariate analyses (HR 0.51, p=0.04). OS was longer for TLS with low fractions of CD21+ B-cells (HR 0.29, p=0.02) and shorter for those with low AID+ fraction of B-cells (HR 2.74, p=0.03).ConclusionsThe presence of TLS in CMMs is associated with improved OS in patients treated with surgery before CBT, but TLS vary widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Importantly, these features have additional prognostic significance, which suggest that some TLS may have regulatory function, while others functioning to support antigen-driven immune responses, depending on the cellular composition and activation status.
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Hummelink, Karlijn, Vincent van der Noort, Mirte Muller, Robert D. Schouten, Michel M. van den Heuvel, Daniela S. Thommen, Egbert F. Smit, Gerrit A. Meijer, and Kim Monkhorst. "Head-to-head comparison of composite and individual biomarkers to predict clinical benefit to PD-1 blockade in non-small cell lung cancer." PLOS ONE 19, no. 7 (July 31, 2024): e0293707. http://dx.doi.org/10.1371/journal.pone.0293707.
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Background The efficacy of PD-1 blocking agents in advanced NSCLC has shown prolonged effectiveness, but only in a minority of patients. Multiple biomarkers have been explored to predict treatment benefit, yet their combined performance remains inadequately examined. In this study, we assessed the combined predictive performance of multiple biomarkers in NSCLC patients treated with nivolumab. Methods Pretreatment samples from 135 patients receiving nivolumab were used to evaluate the predictive performance of CD8 tumor-infiltrating lymphocytes (TILs), intratumoral (IT) localization of CD8 TILs, PD-1 high expressing TILs (PD1T TILs), CD3 TILs, CD20 B-cells, tertiary lymphoid structures (TLS), PD-L1 tumor proportion score (TPS) and the Tumor Inflammation score (TIS). Patients were randomly assigned to a training (n = 55) and validation cohort (n = 80). The primary outcome measure was Disease Control at 6 months (DC 6m) and the secondary outcome measure was DC at 12 months (DC 12m). Results In the validation cohort, the two best performing composite biomarkers (i.e. CD8+IT-CD8 and CD3+IT-CD8) demonstrated similar or lower sensitivity (64% and 83%) and NPV (76% and 85%) compared to individual biomarkers PD-1T TILs and TIS (sensitivity: 72% and 83%, NPV: 86% and 84%) for DC 6m, respectively. Additionally, at 12 months, both selected composite biomarkers (CD8+IT-CD8 and CD8+TIS) demonstrated inferior predictive performance compared to PD-1T TILs and TIS alone. PD-1T TILs and TIS showed high sensitivity (86% and 100%) and NPV (95% and 100%) for DC 12m. PD-1T TILs could more accurately discriminate patients with no long-term benefit, as specificity was substantially higher compared to TIS (74% versus 39%). Conclusion Composite biomarkers did not show improved predictive performance compared to PD-1T TILs and TIS alone for both the 6- and 12-month endpoints. PD-1T TILs and TIS identified patients with DC 12m with high sensitivity. Patients with no long-term benefit to PD-1 blockade were most accurately identified by PD-1T TILs.
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Gonzalez, Ricardo A. Chaurio, Kyle K. Payne, Carmen Maria Anadon Galindo, Tara Lee Costich, Carly Harro, Subir Birwas, Kristen Rigolizzo, et al. "Satb1 deficiency licenses TFH-differentiation and Tertiary Lymphoid Structure formation in cancer." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 89.2. http://dx.doi.org/10.4049/jimmunol.204.supp.89.2.
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Abstract Tertiary Lymphoid Structures (TLS) are commonly identified in human tumors with improved outcome, but how they are orchestrated remains elusive. Here we show that silencing of the master genomic organizer Satb1 results in enhanced antigen-specific T Follicular Helper (TFH) differentiation. Increased TFH thereby promoted antigen-specific intra-tumoral CD19+B220+ B cell responses and spontaneous TLS assembly upon ovarian tumor challenge. Mechanistically, Satb1 deficiency drives increased TFH formation through de-repression of ICOS and PD-1. Accordingly, TGF-β1-driven downregulation of Satb1 licenses activated human CD4+ T-cells for enhanced antigen-specific T Follicular Helper (TFH) differentiation. Furthermore, Satb1 deficiency abrogates the generation of PD-1highCXCR5+Foxp3+ T Follicular Regulatory (TFR) cells during the TFH differentiation process. Importantly, functional TFH cell accumulation, in the absence of Satb1 specifically in CD4+ T cells, resulted in corresponding isotype-switched B cell responses and spontaneous formation of TLS, while B cell depletion accelerated malignant progression. Our results indicate that the formation of TLS in cancer depends on enhanced B cell responses driven by TFH cells generated through Satb1 down-regulation.
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Nader, Noor, Elaine Byrnes, Sheryl Kunning, Thomas Pearce, Gabriel Sica, Timothy Burns, Laura Stabile, Xiaoran Zhang, and Tullia Bruno. "Abstract B005: Lymphoid aggregates dictate immune activity in melanoma and lung brain metastases." Cancer Research 84, no. 5_Supplement_1 (March 4, 2024): B005. http://dx.doi.org/10.1158/1538-7445.brain23-b005.
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Abstract Brain metastasis is the cause of death of more than 40% of all cancer patients and is five times more prevalent than primary brain tumors. Melanoma, lung, and breast cancers are the three most common cancers metastasizing to the brain. Currently, radiation and chemotherapy are the gold standard for the treatment of brain metastasis. However, despite the efficacy of current T cell-based immunotherapies in primary cancers, recent clinical trials have demonstrated little to no benefit in brain metastasis patients. Thus, we predict that tertiary lymphoid structures (TLS) could provide the cellular niches for increased T cell influx and activity. TLS are ectopic lymphoid structures consisting of clusters of B and CD4+ T cells with the presence of high endothelial venules (HEVs) and follicular dendritic cells (FDCs) as hallmarks of TLS formation. B cells and TLS correlate with superior response to immunotherapies and greater overall survival in solid tumors. Despite the positive prognostics of TLS and B cells in solid primary tumors, they are critically understudied in brain metastasis. However, the expression of CXCL13, a key initiating factor of TLS, has been shown to correlate with greater overall survival in melanoma brain metastasis patients. In this study, we hypothesize that B cell infiltration and TLS signatures in brain metastases would correlate with improved anti-tumor immunity and better overall survival. Utilizing multispectral imaging, we demonstrate that despite lacking TLS with canonical hallmarks (HEVs and FDCs), brain metastasis patients have specialized lymphoid structures consisting of proliferating B and T cells, potentially early TLS. We observed that the presence of these lymphoid structures correlates with increased CD8+ T cell infiltration. More specifically, CD8+ T cells are more likely to localize intratumorally in melanoma brain metastasis and in non-tumor regions in LBM patients. Additionally, we identified more active lymphoid aggregates by Ki67 staining in melanoma-brain metastasis patients relative to lung-brain metastasis, suggesting that the primary tumor could influence the type of lymphoid structures in the brain. We also found a correlation between TLS at the primary tumor site and increased B cell infiltration and early TLS formation at the metastatic site in lung cancer patients. Utilizing spatial proteomics and transcriptomics, we aim to carry out an in-depth analysis of the immune activation of the lymphoid structures and key molecular pathways in the tumors of brain metastasis. In conclusion, uncovering differences in B cells and lymphoid aggregates will set the ground truth for structure formation in brain metastases, which will help elucidate key immune targets related to TLS function in these immunologically unique tumors. Citation Format: Noor Nader, Elaine Byrnes, Sheryl Kunning, Thomas Pearce, Gabriel Sica, Timothy Burns, Laura Stabile, Xiaoran Zhang, Tullia Bruno. Lymphoid aggregates dictate immune activity in melanoma and lung brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B005.
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Lucas, Mairi, Zak Kinsella, Claudia Aura Gonzalez, Camille Hurley, Anthony O'Grady, Joanna Fay, Verena Murphy, et al. "The immune microenvironment in hormone positive, HER2 negative breast cancer: A focus on tumour infiltrating lymphocytes, spatial phenotypes and tertiary lymphoid structures." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 2522. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.2522.
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2522 Background: Hormone positive, HER 2 negative breast cancer (ER+/HER2-) has traditionally been considered an immune cold tumour subtype. Research to date indicates that TILs in ER+/HER2- breast cancer may be a negative prognostic marker. However, there is a paucity of data in this area regarding immune subpopulations and spatial phenotypes. Tertiary lymphoid structures (TLS) have been associated with improved prognosis and response to immunotherapy in other solid organ malignancies. We aim to explore the immune microenvironment in early stage ER+/HER2- breast cancer with a focus on tumour infiltrating lymphocytes, spatial phenotypes and tertiary lymphoid structures (TLS). Methods: Full face sections of archival tissue samples from patients with early stage ER+/HER2- breast cancer were stained with CD45 antibody (DAKA clone M0701) via the automated Leica Bond III system. Open source digital pathology analysis software, Qupath, was utilised to identify positive cells and calculate the percentage of positive CD45 staining cells (CD45%) within the tumour area. Spatial analysis was done to divide tumour area into three spatial phenotypes; Immune cold -lacking immune infiltrate;Immune excluded- immune cells restricted to the tumour periphery and immune hot - immune cells infiltrating the tumour core. A tissue micro array (TMA) was created and stained manually with a multiplex chromogenic immunohistochemistry panel for CD20/CD3/DCLamp to identify immune subpopulations associated with tertiary lymphoid structures. Results: A total of 409 patient samples were included in the analysis. 89% (n=367) of samples had a CD45% of 0-10%. CD45% stratification by 21-gene-recurrence score(RS) into Low, Intermediate and High showed a statistically higher CD45% in those with a High RS compared to Low RS (p value= 0.0015). We identified a trend towards worse disease free survival (DFS) in the CD45%high group which did not reach statistical significance. The immune hot spatial phenotype was associated with a worse DFS (p value = 0.034) with no statistically significant difference in DFS between immune cold and immune excluded phenotypes. The majority of samples had minimal immune infiltrate. Staining with a TLS panel revealed that samples with a significant infiltrate could broadly be divided into T cell only infiltrate or those with the presence of TLS, the significance of this is unclear. Conclusions: The majority of ER+/HER2- breast cancer samples had low numbers of TILs, however there is clear heterogeneity within this subgroup. Spatial elements and immune cell subpopulations may further guide the value of TILs in prognosis in this breast cancer subtype.
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Weinstein, Aliyah M., Lu Chen, and Walter J. Storkus. "Modulation of tumor vasculature promotes tertiary lymphoid organogenesis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 213.11. http://dx.doi.org/10.4049/jimmunol.196.supp.213.11.
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Abstract The tumor vasculature has been shown to have pro-tumorigenic effects, leading to the use of anti-angiogenic drugs as therapy. However, the importance of tumor vasculature in recruiting immune cells to the tumor microenvironment (TME), leading to the formation of tertiary lymphoid structures (TLS) within the TME, has also been shown. TLS are aggregates of immune cells that develop at site of chronic inflammation and function as local sites of immune priming. The presence of TLS in the TME is a positive prognostic marker in many human tumors, suggesting that modulation of the tumor vasculature to promote increased TLS formation may serve as a novel therapeutic modality for solid tumors. We have previously shown that intratumorally-injected dendritic cells (DC) engineered to overexpress the Type 1 transactivator Tbet (DC.Tbet) slow tumor progression in a mouse model dependent on T and NK cell recruitment to the TME. Our recent work indicates that DC.Tbet treatment of established murine sarcomas and colon carcinomas leads to an upregulation by d5 following treatment of peripheral node addressin (PNAd) on CD31+ vascular endothelial cells, marking high endothelial venules (HEV) similar to those found in lymph nodes. Dense infiltrates of T cells and DC surround these HEV; however, T cells and DC are observed proximal to tumor vasculature before PNAd upregulation is observed, indicating that while HEV mark mature TLS, PNAd does not initiate TLS formation. Instead, we observe that DC.Tbet but not unmodified DC express CCL21, CXCL13, lymphotoxin (LT) α, and LIGHT. In vivo these can recruit and activate DC, T cells, NK cells, and B cells, which can modulate the vasculature via LT signaling axes to upregulate PNAd and propagate immune cell recruitment to TLS.
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Zou, Xuan, Yu Liu, Xuan Lin, Ruijie Wang, Zhengjie Dai, Yusheng Chen, Mingjian Ma, et al. "Characterization of Estrogen Receptors in Pancreatic Adenocarcinoma with Tertiary Lymphoid Structures." Cancers 15, no. 3 (January 29, 2023): 828. http://dx.doi.org/10.3390/cancers15030828.
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The role of estrogen signaling in antitumor immunology remains unknown for non-traditional sex-biased cancer types such as pancreatic adenocarcinoma (PAAD). Tertiary lymphoid structures (TLS) are active zones composed of multiple types of immune cells, whose presence indicates anti-tumor immune responses. In this study, we employed a 12-chemokine signature to characterize potential gene categories associated with TLS development and identified seventeen major gene categories including estrogen receptors (ERs). Immunohistochemistry staining revealed the expression patterns of three ERs (ERα, ERβ, and GPER) in 174 PAAD samples, and their correlation with clinicopathological characteristics, immune cell infiltration levels, and intratumoral TLS presence was analyzed. The results indicated that ERα (+) and ERβ (+) were correlated with high tumor grade, and ERβ (+) and GPER (+) were correlated with lower TNM stage, and both ERα (+) and GPER (+) displayed a beneficial effect on prognosis in this cohort. Interestingly, positive staining of all three ERs was significantly correlated with the presence of intratumoral TLSs and infiltration of more active immune cells into the microenvironment. Moreover, the chemotaxis of CD8+T-cells to PAAD cells was significantly increased in vitro with upregulated expression of ERα or ERβ on PAAD cells. To conclude, our study showed a novel correlation between ER expression and TLS development, suggesting that ERs may play a protective role by enhancing anti-tumor immune responses in PAAD.
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Li, Songyun, Zhuo Wang, Hsien-Da Huang, and Tzong-Yi Lee. "Machine Learning-Based Characterization and Identification of Tertiary Lymphoid Structures Using Spatial Transcriptomics Data." International Journal of Molecular Sciences 25, no. 7 (March 30, 2024): 3887. http://dx.doi.org/10.3390/ijms25073887.
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Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells in non-lymphoid tissues and are associated with a favorable prognosis in tumors. However, TLS markers remain inconsistent, and the utilization of machine learning techniques for this purpose is limited. To tackle this challenge, we began by identifying TLS markers through bioinformatics analysis and machine learning techniques. Subsequently, we leveraged spatial transcriptomic data from Gene Expression Omnibus (GEO) and built two support vector classifier models for TLS prediction: one without feature selection and the other using the marker genes. The comparable performances of these two models confirm the efficacy of the selected markers. The majority of the markers are immunoglobulin genes, demonstrating their importance in the identification of TLSs. Our research has identified the markers of TLSs using machine learning methods and constructed a model to predict TLS location, contributing to the detection of TLS and holding the promising potential to impact cancer treatment strategies.
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Li, Ziming, Tianxiang Chen, Fengcai Wen, Ding Zhang, Yanan Chen, and Xiaochen Zhao. "Neoadjuvant chemo-immunotherapy increases tumor immune lymphocytes infiltration in resectable NSCLC." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e20573-e20573. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e20573.
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e20573 Background: NCIT (neoadjuvant Chemo-immunotherapy treatment) has revolutionized the treatment of resectable NSCLC due to its better MPR (major pathologic response) rate and pCR (pathologic complete response) rate over neoadjuvant chemotherapy or immunotherapy. However, the intrinsic mechanism underlying this treatment remains unclear. In recent years, the immune microenvironment has attracted considerable attention in the field of immunotherapy. In this study, we explored the relationship between tumor immune lymphocytes (TILs), tertiary lymphoid structures (TLS), and response to NCIT in resectable NSCLC and the change in TILs before and after NCIT. Methods: Twenty-five patients with stage IIA-IIIC NSCLC who underwent surgery after NCIT were enrolled in this retrospective study. Multiplex immunofluorescence (mIF) staining and image analysis assays were performed on the samples collected before and after NCIT for each patient. Results: Among the enrolled patients, 10 achieved MPR or pCR which were defined as response group, whereas 15 did not respond well to NCIT which were defined as non-response group. The results of the mIF assays revealed that NCIT was associated with an increase in immune lymphocytes, including CD3+ (tumor, p = 0.23; stroma, p < 0.01), CD4+ (tumor, p = 0.011; stroma, p < 0.001), CD4+Foxp3+ (tumor, p = 0.63; stroma, p < 0.001), CD8+ (tumor, p = 0.00031; stroma, p < 0.001), CD8+PD-1+ (tumor, p = 0.13; stroma, p = 0.022), PD-L1+CD68+ (tumor, p = 0.85; stroma, p = 0.041), and TLS (tertiary lymphoid structures, p = 0.00027). The comparison of TIL between response group and non-response group revealed that CD3, FOXP3+, and CD8+PD-1+ may serve as predictors of the response to neoadjuvant immunotherapy. Conclusions: To our knowledge, this is the first study to explore the relationship between TILs, TLS, and response to NCIT and TIL changes during NCIT in resectable Chinese NSCLC. In resectable NSCLC, the infiltration of immune cells before NCIT was correlated with the pathologic complete response, which enhanced the TILs as a promising predictor for selecting patients who were more likely to benefit from NCIT.
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Deng, Shuzhe, Xinxin Yang, Lin He, Yunjing Hou, and Hongxue Meng. "Tertiary Lymphoid Structures in Microorganism-Related Cancer." Cancers 16, no. 20 (October 12, 2024): 3464. http://dx.doi.org/10.3390/cancers16203464.
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Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues formed by the accumulation of lymphocytes and other components outside lymphoid organs. They have been shown to be widespread in cancers and have predictive effects on prognosis and immunotherapy efficacy; however, there is no standardized measurement guide. This paper provides a reference for future research. Moreover, the induction strategy for the formation mechanism of TLSs is a new direction for future cancer treatment, such as cancer vaccines for microorganisms. The effects of microorganisms on cancer are dual. The role of microorganisms, including bacteria, parasites, viruses, and fungi, in promoting cancer has been widely confirmed. However, the specific mechanism of their tumor suppressor effect, particularly the promotion of TLS formation, is currently unknown. In this review, we summarize the role of TLSs in cancer related to microbial infection and provide new ideas for further understanding their mechanisms of action in cancer.
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Berthe, Julie, Felix Segerer, Emily C. Jennings, Alma Andoni, Marco Testori, Megha Saraiya, Miljenka Vuko, et al. "Abstract 1711: A multi-modal analysis approach leveraging multiplexed spatial phenotyping and multi-omics analysis to better understand the prognostic value of tertiary lymphoid structures in non-small cell lung cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1711. http://dx.doi.org/10.1158/1538-7445.am2022-1711.
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Abstract Introduction: Tertiary 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. 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. Methods: With the aim of gaining insights into TLS biology and evaluating the prognostic role of TLS in Non-Small Cell Lung Carcinoma (NSCLC) according to their multiple features, we developed a TLS multiplex immunofluorescent (mIF) panel that includes T cell (CD3, CD8), B cell (CD20), Follicular Dendritic cell (CD21, CD23) and mature dendritic cell (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). 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. Results: Assessment of the prevalence of each cell phenotype within the tumor tissue and TLS (tumor centre vs invasive margin; tumor epithelium vs stroma), 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 these 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. Conclusion: This 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 NSCLC patient outcomes to evaluate in the clinic. Citation Format: Julie Berthe, Felix Segerer, Emily C. Jennings, Alma Andoni, Marco Testori, Megha Saraiya, Miljenka Vuko, Harald Hessel, Andreas Spitzmüller, Mari Heininen-Brown, Jorge Blando, Felicia Ng, Emma Jones, Sophie Willis, Michael Surace, Rieneke van de Ven, Tanja De Gruijl, Helen Angell. A multi-modal analysis approach leveraging multiplexed spatial phenotyping and multi-omics analysis to better understand the prognostic value of tertiary lymphoid structures in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1711.
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Rodriguez, Anthony B., J. David Peske, Amber N. Woods, Marit Martina Melssen, Salwador Cyranowski, Geoffrey Raymond Parriott, and Victor H. Engelhard. "Cellular and molecular mechanisms regulating the development of tertiary lymphoid structures in tumor." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 178.10. http://dx.doi.org/10.4049/jimmunol.200.supp.178.10.
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Abstract Tertiary lymphoid structures (TLS) have been described in association with several tumor types, and they are usually associated with enhanced patient survival. However, mechanisms regulating their formation remain unknown. We found that intra- and peri-tumoral TLS develop in intraperitoneal (IP) but not subcutaneously (SC) implanted tumors. These TLS are characterized by a robust accumulation of B cells, and an associated reticular network of podoplanin+ fibroblasts expressing high levels of CXCL12, CXCL13, and the B-cell survival factors BAFF and APRIL. These results suggest that IP tumor-associated fibroblasts are polarized into organizer cells that orchestrate TLS formation. We’ve previously demonstrated that CD8 T effectors induce the development of lymph node-like vasculature in IP tumors. To determine whether these cells also regulate TLS development, we evaluated IP tumors grown in Rag1−/− mice and Rag1−/− mice repleted with bulk CD8 T cells. CD8 T cells upregulated the number of podoplanin+ fibroblasts and CXCL12 expression. However, CXCL13, BAFF and APRIL expression was not dependent on CD8 T cells. Thus, the representation of podoplanin+ fibroblasts and their expression of CXCL12 is regulated by adaptive immunity, while their expression of CXCL13, BAFF and APRIL is mediated by an innate element within the IP tumor microenvironment. We also found that increasing the load of the model tumor antigen ovalbumin led to an increased formation of peri-tumoral TLS with a classical organization, on top of the non-classical intratumoral structures evident at a low antigen load. These results identify novel mechanisms regulating different elements involved in organizing tumor-associated TLS.
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Mannarino, Laura, Lara Paracchini, Federica Pezzuto, Gheorghe Emilian Olteanu, Laura Moracci, Luca Vedovelli, Irene De Simone, et al. "Epithelioid Pleural Mesothelioma Is Characterized by Tertiary Lymphoid Structures in Long Survivors: Results from the MATCH Study." International Journal of Molecular Sciences 23, no. 10 (May 21, 2022): 5786. http://dx.doi.org/10.3390/ijms23105786.
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Pleural mesothelioma (PM) is an aggressive tumor with few therapeutic options. Although patients with epithelioid PM (ePM) survive longer than non-epithelioid PM (non-ePM), heterogeneity of tumor response in ePM is observed. The role of the tumor immune microenvironment (TIME) in the development and progression of PM is currently considered a promising biomarker. A few studies have used high-throughput technologies correlated with TIME evaluation and morphologic and clinical data. This study aimed to identify different morphological, immunohistochemical, and transcriptional profiles that could potentially predict the outcome. A retrospective multicenter cohort of 129 chemonaive PM patients was recruited. Tissue slides were reviewed by dedicated pathologists for histotype classification and immunophenotype of tumor-infiltrating lymphocytes (TILs) and lymphoid aggregates or tertiary lymphoid structures (TLS). ePM (n = 99) survivors were further classified into long (>36 months) or short (<12 months) survivors. RNAseq was performed on a subset of 69 samples. Distinct transcriptional profiling in long and short ePM survivors was found. An inflammatory background with a higher number of B lymphocytes and a prevalence of TLS formations were detected in long compared to short ePM survivors. These results suggest that B cell infiltration could be important in modulating disease aggressiveness, opening a pathway for novel immunotherapeutic approaches.
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Mizuta, Ryo, Daisuke Muraoka, Ayako Okamura, Takanari Okamoto, Shota Nohira, Yoshihiro Otani, Joji Ishida, Kentaro Fujii, Isao Date, and Hirokazu Matsushita. "10036-IM-3 SPATIAL AND GENOMIC ANALYSES FOR THE CONSTRUCTION OF TERTIARY LYMPHOID STRUCTURE IN GLIOBLASTOMA." Neuro-Oncology Advances 5, Supplement_5 (December 1, 2023): v5—v6. http://dx.doi.org/10.1093/noajnl/vdad141.020.
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Abstract BACKGROUND Recently, the presence of tertiary lymphoid structure (TLS), composed mainly of intratumoral B cells, has been reported as a favorable prognostic factor in various types of cancer. However, in glioblastoma, TLS has not been well studied though increased B-cell infiltration was likely to be related to improved prognosis. In this study, we performed spatial and genomic analyses in human glioblastoma, focusing on TLS. METHODS We evaluated lymphocytic infiltration by immunostaining in 54 cases. Flow cytometry was conducted on 12 prospective samples. RNA-sequencing (RNA-seq) was performed in 43 cases to compare those with and without TLS by differential gene expression (DGE) analysis and Gene Set Enrichment Analysis (GSEA). RESULTS TLS was detected in 5 (9.3%) of the 54 cases. Flow cytometry showed that 3 cases with TLS by immunostaining had higher numbers of T and B cells than those without TLS. DGE analysis showed increased gene expression related to the T cell activation marker (TNFRSF9), chemokine (CCL5), etc., in patients with TLS. GSEA also confirmed the activation of immune responses such as adaptive immune response and B cell receptor signaling pathway. We are currently validating these data with spatial transcriptome analysis and investigating the TLS formation in detail. DISCUSSION Although several TLS signatures and TLS components have been reported so far, the formation mechanism of TLS is still unknown. In addition, to our knowledge, there are no reports yet on spatial transcriptome analysis in multiple cases of glioblastoma focusing on the presence of TLS. CONCLUSION We analyzed a total of 54 glioblastoma cases by immunostaining. RNA-seq and spatial transcriptome analysis were performed to assess TLS in glioblastoma comprehensively.
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Luo, Ran, Dan Chang, Nanhui Zhang, Yichun Cheng, Shuwang Ge, and Gang Xu. "T Follicular Helper Cells in Tertiary Lymphoid Structure Contribute to Renal Fibrosis by IL-21." International Journal of Molecular Sciences 24, no. 16 (August 8, 2023): 12535. http://dx.doi.org/10.3390/ijms241612535.
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Tertiary lymphoid structure (TLS) represents lymphocyte clusters in non-lymphoid organs. The formation and maintenance of TLS are dependent on follicular helper T (TFH) cells. However, the role of TFH cells during renal TLS formation and the renal fibrotic process has not been comprehensively elucidated in chronic kidney disease. Here, we detected the circulating TFH cells from 57 IgAN patients and found that the frequency of TFH cells was increased in IgA nephropathy patients with renal TLS and also increased in renal tissues from the ischemic-reperfusion-injury (IRI)-induced TLS model. The inducible T-cell co-stimulator (ICOS) is one of the surface marker molecules of TFH. Remarkably, the application of an ICOS-neutralizing antibody effectively prevented the upregulation of TFH cells and expression of its canonical functional mediator IL-21, and also reduced renal TLS formation and renal fibrosis in IRI mice in vivo. In the study of this mechanism, we found that recombinant IL-21 could directly promote renal fibrosis and the expression of p65. Furthermore, BAY 11-7085, a p65 selective inhibitor, could effectively alleviate the profibrotic effect induced by IL-21 stimulation. Our results together suggested that TFH cells contribute to TLS formation and renal fibrosis by IL-21. Targeting the ICOS-signaling pathway network could reduce TFH cell infiltration and alleviate renal fibrosis.
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Tseng, William W., Shruti Malu, Minying Zhang, Jieqing Chen, Geok Choo Sim, Wei Wei, Davis Ingram, et al. "Analysis of the Intratumoral Adaptive Immune Response in Well Differentiated and Dedifferentiated Retroperitoneal Liposarcoma." Sarcoma 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/547460.
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Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease.
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Tao, Ping, Zhenyu Wang, Jiongyuan Wang, Jun Chen, Liang Hong, Lijie Ma, Yong Zhang, and Hanxing Tong. "Integrated multi-omics analysis reveals immune landscape of tertiary lymphoid structure in retroperitoneal liposarcoma." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 11563. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.11563.
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11563 Background: Retroperitoneal liposarcoma (RPLS) is a rare type of mesenchymal tumor characterized by difficult surgical management, immune desert, poor response to immunotherapy and high local recurrence rate. However, how tertiary lymphoid structures (TLS) dictates complex biological processes such as antitumor immunity remains unknown. Thus, we aimed to investigate the spatio-temporal heterogeneity of TLS formation, maturation, and functional involvement in TIME, and the clinical value of TLS in multiple retrospective RPLS clinical cohorts. Methods: 330 patients were retrospectively enrolled into five independent cohorts from the two largest retroperitoneal tumor research centers in China and the TCGA database. Single-cell RNA sequencing (sc-RNA seq) (n=4) and spatial transcriptome seq (n=2) were performed for the estimation of TIME based on treatment-naive RPLS. Transcriptomic profiles of 309 cases in five cohorts were obtained from the ZSFD, GEO, and TCGA databases. TLS was quantified in three different anatomic subregions (intra-tumor, invasion margin and peri-tumor) and correlated with overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis. Multiplex immunohistochemistry (mIHC) was performed to characterize and validate the spatial composition of TLS in another treatment-naive RPLS cohort (n=16), neoadjuvant chemotherapy (n=12) and neoadjuvant radiotherapy (n=20) RPLS cohorts. Results: The joint scoring system of T and P scores stratified RPLS into four immune classes with different TLS distribution patterns and prognoses (p<0.001). The immune class C-index was significantly higher than the TNM staging system (0.798 vs. 0.62, p=0.005). Importantly, mIHC revealed that regulatory T cells (Tregs) and M2 phenotype tumor-associated macrophages (TAMs) were significantly increased in intra-tumoral TLS in DDLPS compared to WDLPS, showing an immunosuppressive pattern. Strikingly, neoadjuvant chemotherapy and radiotherapy could block this status of immunosuppressive, induced TLS formation and restore the antitumor immune balance with significantly more CD38+IgG+ plasma cells (PCs) in responsive RPLS, whereas non-responsive RPLS deteriorated into a more suppressive one. Sc-RNA Seq and ST analysis further revealed significant intra- and inter-tumoral TIME heterogeneity and identified the underlying transcriptomic programs driving each phenotype. Conclusions: Our study provides a high-resolution map of TIME in treatment-naive and neoadjuvant chemotherapy/radiotherapy RPLS. Effective neoadjuvant chemotherapy and radiotherapy can induce TLS formation and restore the antitumor immune balance in RPLS.
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Cheng, Na, Peng Li, Huanhuan Cheng, Xiaoxiao Zhao, Min Dong, Yiwang Zhang, Peizhen Zhao, Jianning Chen, and Chunkui Shao. "Prognostic Value of Tumor-Infiltrating Lymphocytes and Tertiary Lymphoid Structures in Epstein-Barr Virus-Associated and -Negative Gastric Carcinoma." Frontiers in Immunology 12 (July 1, 2021). http://dx.doi.org/10.3389/fimmu.2021.692859.
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BackgroundTumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response against cancer and tertiary lymphoid structures (TLS) may contribute to lymphocytes recruitment. Both of them have been reported as potential prognostic parameters in some human malignancies. However, the roles of TILs, TLS, and their correlation in Epstein-Barr Virus-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC) are largely unknown.MethodsTo observe the correlation among TILs, TLS, and clinicopathological characteristics and their prognostic significance in EBVaGC and EBVnGC, respectively. TILs and TLS were assessed by morphology and/or immunohistochemistry, and accompanied by clinicopathological analysis from 846 gastric cancer patients in multiple institutions.ResultsForty-two (5.0%) cases of EBVaGC and 804 cases of EBVnGC were identified by in situ hybridization, respectively. For EBVnGC, higher TILs grade was correlated with TLS-present. EBVnGC patients with high TILs grade and TLS-present exhibited survival benefits. TILs (P = 0.001) and TLS (P = 0.003), especially TILs & TLS (P < 0.001) were independent prognostic factors in EBVnGC. A nomogram was constructed and validated for predicting the probability of overall survival and performed well with a good calibration. No significant prognostic value was detected in EBVaGC.ConclusionTILs and TLS, especially TILs & TLS were promising prognostic indicators for overall survival in EBVnGC. TILs and TLS were highly overlapping in their extent and prognostic abilities, and may be considered as a coindicator of prognosis of gastric cancer. The evaluations of TILs and TLS are simple and can be assessed routinely in pathological diagnosis.
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Vaccaro, Alessandra, Tiarne van de Walle, Mohanraj Ramachandran, Magnus Essand, and Anna Dimberg. "Of mice and lymphoid aggregates: modeling tertiary lymphoid structures in cancer." Frontiers in Immunology 14 (October 26, 2023). http://dx.doi.org/10.3389/fimmu.2023.1275378.
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Tertiary lymphoid structures (TLS) are lymph node-like aggregates that can form in association with chronic inflammation or cancer. Mature TLS are organized into B and T cell zones, and are not encapsulated but include all cell types necessary for eliciting an adaptive immune response. TLS have been observed in various cancer types and are generally associated with a positive prognosis as well as increased sensitivity to cancer immunotherapy. However, a comprehensive understanding of the roles of TLS in eliciting anti-tumor immunity as well as the mechanisms involved in their formation and function is still lacking. Further studies in orthotopic, immunocompetent cancer models are necessary to evaluate the influence of TLS on cancer therapies, and to develop new treatments that promote their formation in cancer. Here, we review key insights obtained from functional murine studies, discuss appropriate models that can be used to study cancer-associated TLS, and suggest guidelines on how to identify TLS and distinguish them from other antigen-presenting niches.
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Schumacher, Ton N., and Daniela S. Thommen. "Tertiary lymphoid structures in cancer." Science 375, no. 6576 (January 7, 2022). http://dx.doi.org/10.1126/science.abf9419.
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Tertiary lymphoid structures in cancer Tertiary lymphoid structures (TLSs) are lymphoid formations that are found in nonlymphoid tissues. TLS can develop in inflamed tissues and are associated with chronic inflammatory disorders, autoimmunity, and cancer. In the setting of tumors, TLSs facilitate the influx of immune cells into the tumor site and have therefore attracted interest as a means of improving anticancer immunity and favorable treatment response in patients. Schumacher and Thommen review the biology of TLSs and outline recent advances in TLS research. They discuss how TLSs are detected and defined, the mechanism(s) of formation in cancer, and the potential of targeting TLSs for therapeutic benefit. —PNK
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Li, Qunxing, Xiangqi Liu, Dikan Wang, Yanqiong Wang, Huanzi Lu, Shuqiong Wen, Juan Fang, Bin Cheng, and Zhi Wang. "Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma." International Journal of Oral Science 12, no. 1 (September 15, 2020). http://dx.doi.org/10.1038/s41368-020-00092-3.
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Abstract Tertiary lymphoid structures (TLS) are ectopic lymphoid structures in cancers that are largely associated with favourable prognosis. However, the prognostic value of TLSs in oral squamous cell carcinoma (OSCC) is largely unknown, and the association between tumour infiltrating lymphocytes (TILs) and TLSs has been rarely explored in OSCC. In this study, associated markers of TLS, including peripheral node address (PNAd) in high endothelial venules, CD20 in B cells and CD3 in T cells, were examined in 168 OSCC patients, and survival analysis was performed between TLS-positive and TLS-negative cohorts. We detected the presence of TILs by staining CD8+ cytotoxic T cells and CD57+ NK cells as well. TLSs appeared as highly organized structures in 45 (26.8%) cases. TLS-positive patients had a better 5-year overall survival (OS) rate (88.9% vs. 56.1%, P < 0.001) and relapse-free survival (RFS) rate (88.9% vs. 63.4%, P = 0.002). Moreover, the presence of TLS was an independent prognostic factor for both the 5-year OS rate (hazard ratio [HR] = 3.784; 95% confidence interval [CI], 1.498–9.562) and RFS rate (HR = 3.296; 95% CI, 1.279–8.490) in multivariate analysis. Furthermore, a higher density of CD8+ T cells and CD57+ NK cells was found in TLS-positive sections than in TLS-negative counterparts (P < 0.001), and their combination provided a higher predictive accuracy (AUC = 0.730; 95% CI, 0.654–0.805). In conclusion, our results suggest that TLS is an independent positive prognostic factor for OSCC patients. These findings provide a theoretical basis for the future diagnostic and therapeutic value of TLSs in OSCC treatment.
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"Probing Microbiome, TLS Dynamics in Tumors." Cancer Discovery, December 5, 2022, OF1. http://dx.doi.org/10.1158/2159-8290.cd-nb2022-0077.
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Abstract Across several cancer types, researchers have identified distinct gut microbial features that are associated with a high density of intratumoral tertiary lymphoid structures. They hope to develop microbiome-based interventions that induce the formation of more of these structures, which correlate with immune checkpoint blockade responsiveness.
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You, Xin, Kristina Koop, and Andreas Weigert. "Heterogeneity of tertiary lymphoid structures in cancer." Frontiers in Immunology 14 (December 4, 2023). http://dx.doi.org/10.3389/fimmu.2023.1286850.
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The success of immunotherapy approaches, such as immune checkpoint blockade and cellular immunotherapy with genetically modified lymphocytes, has firmly embedded the immune system in the roadmap for combating cancer. Unfortunately, the majority of cancer patients do not yet benefit from these therapeutic approaches, even when the prognostic relevance of the immune response in their tumor entity has been demonstrated. Therefore, there is a justified need to explore new strategies for inducing anti-tumor immunity. The recent connection between the formation of ectopic lymphoid aggregates at tumor sites and patient prognosis, along with an effective anti-tumor response, suggests that manipulating the occurrence of these tertiary lymphoid structures (TLS) may play a critical role in activating the immune system against a growing tumor. However, mechanisms governing TLS formation and a clear understanding of their substantial heterogeneity are still lacking. Here, we briefly summarize the current state of knowledge regarding the mechanisms driving TLS development, outline the impact of TLS heterogeneity on clinical outcomes in cancer patients, and discuss appropriate systems for modeling TLS heterogeneity that may help identify new strategies for inducing protective TLS formation in cancer patients.
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Chen, Yulu, Yuhao Wu, Guorong Yan, and Guolong Zhang. "Tertiary lymphoid structures in cancer: maturation and induction." Frontiers in Immunology 15 (April 16, 2024). http://dx.doi.org/10.3389/fimmu.2024.1369626.
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Tertiary lymphoid structure (TLS) is an ectopic lymphocyte aggregate formed in peripheral non-lymphoid tissues, including inflamed or cancerous tissue. Tumor-associated TLS serves as a prominent center of antigen presentation and adaptive immune activation within the periphery, which has exhibited positive prognostic value in various cancers. In recent years, the concept of maturity regarding TLS has been proposed and mature TLS, characterized by well-developed germinal centers, exhibits a more potent tumor-suppressive capacity with stronger significance. Meanwhile, more and more evidence showed that TLS can be induced by therapeutic interventions during cancer treatments. Thus, the evaluation of TLS maturity and the therapeutic interventions that induce its formation are critical issues in current TLS research. In this review, we aim to provide a comprehensive summary of the existing classifications for TLS maturity and therapeutic strategies capable of inducing its formation in tumors.
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Wang, Qianyu, Wentao Zhong, Xiaofei Shen, Zechen Hao, Meng Wan, Xiaopeng Yang, Ran An, et al. "Tertiary lymphoid structures predict survival and response to neoadjuvant therapy in locally advanced rectal cancer." npj Precision Oncology 8, no. 1 (March 2, 2024). http://dx.doi.org/10.1038/s41698-024-00533-w.
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AbstractTertiary lymphoid structure (TLS) contributes to the anti-tumor immune response, and predicts the prognosis of colorectal cancer patients. However, the potential impact of TLS in shaping the immune status of rectal adenocarcinoma, and the intrinsic relationship between TLS and neoadjuvant therapies (neoTx) remain unclear. We performed hematoxylin-eosin staining, immunohistochemical and biomolecular analyses to investigate TLS and tumor-infiltrating lymphocytes (TILs) in 221 neoTx-treated and 242 treatment-naïve locally advanced rectal cancer (LARC) patients. High TLS density was significantly associated with the absence of vascular invasion, a lower neutrophil-to-lymphocyte ratio, increased TLS maturity, a longer recurrence-free survival (RFS) (hazard ratio [HR] 0.2985 95% confidence interval [CI] 0.1894–0.4706, p < 0.0001) and enhanced infiltration of adaptive immune cells. Biomolecular analysis showed that high TLS-score was strongly associated with more infiltration of immune cells and increased activation of immune-related pathways. TLS+ tumors in pre-treatment specimens were associated with a higher proportion of good respond (62.5% vs. 29.8%, p < 0.0002) and pathological complete remission (pCR) (40.0% vs. 11.1%, p < 0.0001), and significantly increased RFS (HR 0.3574 95%CI 0.1489–0.8578 p = 0.0213) compared with TLS- tumors in the neoTx cohort, which was confirmed in GSE119409 and GSE150082. Further studies showed that neoTx significantly reduced TLS density and maturity, and abolished the prognostic value of TLS. Our study illustrates that TLS may have a key role in mediating the T-cell-inflamed tumor microenvironment, which also provides a new direction for neoTx, especially neoadjuvant immunotherapy, in LRAC patients.
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Sun, Guojuan, and Yi Liu. "Tertiary lymphoid structures in ovarian cancer." Frontiers in Immunology 15 (November 6, 2024). http://dx.doi.org/10.3389/fimmu.2024.1465516.
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Ovarian cancer (OC) is a significant cause of cancer-related mortality in women worldwide. Despite advances in treatment modalities, including surgery and chemotherapy, the overall prognosis for OC patients remains poor, particularly for patients with advanced or recurrent disease. Immunotherapy, particularly immune checkpoint blockade (ICB), has revolutionized cancer treatment in various malignancies but has shown limited efficacy in treating OC, which is primarily attributed to the immunologically. Tertiary lymphoid structures (TLSs), which are ectopic aggregates of immune cells, have emerged as potential mediators of antitumor immunity. This review explores the composition, formation, and induction of tumor associated TLS (TA-TLS) in OC, along with their role and therapeutic implications in disease development and treatment. By elucidating the roles TA-TLSs and their cellular compositions played in OC microenvironment, novel therapeutic targets may be identified to overcome immune suppression and enhance immunotherapy efficacy in ovarian cancer.
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Gkegka, Anastasia G., Michael I. Koukourakis, Michael Katotomichelakis, and Alexandra Giatromanolaki. "Cancer Microenvironment Defines Tumor-Infiltrating Lymphocyte Density and Tertiary Lymphoid Structure Formation in Laryngeal Cancer." Head and Neck Pathology, December 31, 2022. http://dx.doi.org/10.1007/s12105-022-01517-7.
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Abstract Background The presence and activity of tumor-infiltrating lymphocytes (TILs) is a key parameter related to the antitumor immune response. A large number of studies reveal TIL density as a prognostic marker and predictor of response to radiotherapy, chemotherapy, and immunotherapy. Methods We examined the TIL and tertiary lymphoid structure TLS density in the invading front and inner tumor stroma, in a 33 squamous cell laryngeal carcinomas (LSCC) treated with laryngectomy. TIL and TLS densities were in parallel examined with markers of anaerobic metabolism, vascular density (VD), vascular survival ability (VSA), and histopathological parameters. Results TIL and TLS densities significantly decreased in inner tumor areas (p < 0.0001). TIL density in the invading tumor front was inversely related with lymph node involvement (p = 0.03), HIF1α expression (p = 0.008), vessel density (p = 0.02), and MIB1 (p = 0.006). TIL density in inner stroma was inversely linked to local invasion (marginal p = 0.05), tumor budding (TB) (p = 0.005), MIB1 (p = 0.02), and HIF1α expression (p = 0.02). Low-TLS density in the invading front and in inner tumor areas was related to high TB (p = 0.02 and 0.002, respectively), HIF1α (p = 0.003 and 0.01, respectively), and LDH5 expression (p = 0.003 and 0.007, respectively). CD4+, FOXP3+ TIL density, and FOXP3+/CD8+ ratio were directly associated with VSA (p = 0.008, 0.02, and 0.05, respectively). Conclusion Poor immune response is related to hypoxic background and anaerobic metabolism, as well as increased invasive and metastatic ability. Regulatory TIL markers are linked with increased angiogenic potential. The prognostic, predictive, and therapy-guiding value of TILs in clinical practice demands thorough investigation.
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Zhang, Yuyuan, Mengjun Xu, Yuqing Ren, Yuhao Ba, Shutong Liu, Anning Zuo, Hui Xu, Siyuan Weng, Xinwei Han, and Zaoqu Liu. "Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application." Molecular Cancer 23, no. 1 (April 6, 2024). http://dx.doi.org/10.1186/s12943-024-01980-6.
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AbstractTertiary lymphoid structures (TLS) are clusters of immune cells that resemble and function similarly to secondary lymphoid organs (SLOs). While TLS is generally associated with an anti-tumour immune response in most cancer types, it has also been observed to act as a pro-tumour immune response. The heterogeneity of TLS function is largely determined by the composition of tumour-infiltrating lymphocytes (TILs) and the balance of cell subsets within the tumour-associated TLS (TA-TLS). TA-TLS of varying maturity, density, and location may have opposing effects on tumour immunity. Higher maturity and/or higher density TLS are often associated with favorable clinical outcomes and immunotherapeutic response, mainly due to crosstalk between different proportions of immune cell subpopulations in TA-TLS. Therefore, TLS can be used as a marker to predict the efficacy of immunotherapy in immune checkpoint blockade (ICB). Developing efficient imaging and induction methods to study TA-TLS is crucial for enhancing anti-tumour immunity. The integration of imaging techniques with biological materials, including nanoprobes and hydrogels, alongside artificial intelligence (AI), enables non-invasive in vivo visualization of TLS. In this review, we explore the dynamic interactions among T and B cell subpopulations of varying phenotypes that contribute to the structural and functional diversity of TLS, examining both existing and emerging techniques for TLS imaging and induction, focusing on cancer immunotherapies and biomaterials. We also highlight novel therapeutic approaches of TLS that are being explored with the aim of increasing ICB treatment efficacy and predicting prognosis.
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Salem, Deepak, Manoj Chelvanambi, Walter J. Storkus, and Ronald J. Fecek. "Cutaneous Melanoma: Mutational Status and Potential Links to Tertiary Lymphoid Structure Formation." Frontiers in Immunology 12 (March 4, 2021). http://dx.doi.org/10.3389/fimmu.2021.629519.
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Recent advances in immunotherapy have enabled rapid evolution of novel interventional approaches designed to reinvigorate and expand patient immune responses against cancer. An emerging approach in cancer immunology involves the conditional induction of tertiary lymphoid structures (TLS), which are non-encapsulated ectopic lymphoid structures forming at sites of chronic, pathologic inflammation. Cutaneous melanoma (CM), a highly-immunogenic form of solid cancer, continues to rise in both incidence and mortality rate, with recent reports supporting a positive correlation between the presence of TLS in melanoma and beneficial treatment outcomes amongst advanced-stage patients. In this context, TLS in CM are postulated to serve as dynamic centers for the initiation of robust anti-tumor responses within affected regions of active disease. Given their potential importance to patient outcome, significant effort has been recently devoted to gaining a better understanding of TLS neogenesis and the influence these lymphoid organs exert within the tumor microenvironment. Here, we briefly review TLS structure, function, and response to treatment in the setting of CM. To uncover potential tumor-intrinsic mechanisms that regulate TLS formation, we have taken the novel perspective of evaluating TLS induction in melanomas impacted by common driver mutations in BRAF, PTEN, NRAS, KIT, PRDM1, and MITF. Through analysis of The Cancer Genome Atlas (TCGA), we show expression of DNA repair proteins (DRPs) including BRCA1, PAXIP, ERCC1, ERCC2, ERCC3, MSH2, and PMS2 to be negatively correlated with expression of pro-TLS genes, suggesting DRP loss may favor TLS development in support of improved patient outcome and patient response to interventional immunotherapy.
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Liu, Zhonglong, Xiaoyan Meng, Xiao Tang, Weili Zou, and Yue He. "Intratumoral tertiary lymphoid structures promote patient survival and immunotherapy response in head neck squamous cell carcinoma." Cancer Immunology, Immunotherapy, December 8, 2022. http://dx.doi.org/10.1007/s00262-022-03310-5.
Full textAbstract:
AbstractTertiary lymphoid structures (TLSs) hold the potential role in the prediction of immunotherapy response in several clinical trials. TLSs in head neck squamous cell carcinoma (HNSCC) have been investigated through IHC analysis, whereas there is no TLS gene signature to evaluate the level of TLS neogenesis. We here proposed a TLS signature containing 13 chemokines and determined TLS-hi and TLS-low groups in HNSCC samples from The Cancer Genome Atlas. TLS-hi condition signified a better overall survival. A more inflamed immune infiltrative landscape was identified in the TLS-hi tumors characterized by higher proportion of T cells, TCR/BCR activation and antigen processing. High level of TLSs has a determined role in the clinical significance of T cells. Interesting discovery was that innate lymphoid cells and cancer-associated fibroblasts were positively associated with TLS neogenesis in TME of HNSCC. Furthermore, by integrated TLSs with stromal cells and score, immune cells and score, TMB and malignant cells, we proposed a novel HNSCC TME classifications (HNSCC-TCs 1–5), unravelling the counteracted role of stromal cells and score in inflamed immune landscape, which may provide a novel stromal targeted modality in HNSCC therapy. Finally, we verified that TLS statue is an ideal predictor for immune checkpoint blockade immunotherapy. Current study indicated that the TLSs serve as a novel prognostic biomarker and predictor for immunotherapy, which may provide directions to the current investigations on immunotherapeutic strategies for HNSCC.
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Byers, Candice, Melissa Gill, Nicholas R. Kurtansky, Christi Alessi-Fox, Maggie Harman, Miguel Cordova, Salvador Gonzalez, et al. "Tertiary lymphoid structures accompanied by fibrillary matrix morphology impact anti-tumor immunity in basal cell carcinomas." Frontiers in Medicine 9 (October 27, 2022). http://dx.doi.org/10.3389/fmed.2022.981074.
Full textAbstract:
Tertiary lymphoid structures (TLS) are specialized lymphoid formations that serve as local repertoire of T- and B-cells at sites of chronic inflammation, autoimmunity, and cancer. While presence of TLS has been associated with improved response to immune checkpoint blockade therapies and overall outcomes in several cancers, its prognostic value in basal cell carcinoma (BCC) has not been investigated. Herein, we determined the prognostic impact of TLS by relating its prevalence and maturation with outcome measures of anti-tumor immunity, namely tumor infiltrating lymphocytes (TILs) and tumor killing. In 30 distinct BCCs, we show the presence of TLS was significantly enriched in tumors harboring a nodular component and more mature primary TLS was associated with TIL counts. Moreover, assessment of the fibrillary matrix surrounding tumors showed discrete morphologies significantly associated with higher TIL counts, critically accounting for heterogeneity in TIL count distribution within TLS maturation stages. Specifically, increased length of fibers and lacunarity of the matrix with concomitant reduction in density and alignment of fibers were present surrounding tumors displaying high TIL counts. Given the interest in inducing TLS formation as a therapeutic intervention as well as its documented prognostic value, elucidating potential impediments to the ability of TLS in driving anti-tumor immunity within the tumor microenvironment warrants further investigation. These results begin to address and highlight the need to integrate stromal features which may present a hindrance to TLS formation and/or effective function as a mediator of immunotherapy response.