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Cook, Seungho, Haenara Shin, Mi-Kyoung Seo, Dae Seung Lee, and Hongyoon Choi. "Abstract 5420: Deep learning-based mapping of tertiary lymphoid structure scores from H&E images of renal cell carcinoma trained by spatial transcriptomics data." Cancer Research 83, no. 7_Supplement (2023): 5420. http://dx.doi.org/10.1158/1538-7445.am2023-5420.
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Abstract Purpose Tertiary lymphoid structures are organized aggregates of immune cells present in the tumor microenvironment (TME) in which novel targets as well as beneficial biomarkers for immunotherapy in cancer were found. Here, we have developed and validated a deep learning model by integrating H&E images of renal cell carcinoma and spatial transcriptomics data to infer spatial mapping of tertiary lymphoid structure scores in TME only using hematoxylin and eosin (H&E) images. Methods A total of 20 H&E images combined with spatial transcriptomics data of renal cell carcinoma were used to develop a model. Tertiary lymphoid structure scores can be acquired for each spot in spatial transcriptomics by geometric mean of the specific gene expression relevant to B cell, T cell, immunoglobulin, fibroblast, complement, and others. A convolutional neural network using H&E image patches as inputs was developed to predict the tertiary lymphoid structure scores from H&E-stained tissue image patches of renal cell carcinoma acquired by different patients. For the external validation, the model estimated the tertiary lymphoid structure scores from H&E-stained tissue image patches of renal cell carcinoma of The Cancer Genome Atlas (TCGA-RCC). Results The tertiary lymphoid structure scores inferred by the model using H&E image patches were significantly correlated with those derived by spatial transcriptomics data as an internal validation (r = 0.68, p < 1e-10). The mean value of the deep learning-based tertiary lymphoid structure scores estimated by the TCGA-RCC tissue images was significantly correlated with the tertiary lymphoid structure scores, T cell enrichment scores and immune cell enrichment scores estimated by bulk RNA-seq data from the corresponding TCGA data. Conclusions A deep learning model to infer spatial tertiary lymphoid structure in the tumor microenvironment using H&E images was developed. As the tertiary lymphoid structure is a key to predict responsiveness of immune checkpoint inhibitors, mapping the score only using H&E images could be clinically translated into image-based biomarkers. This approach can provide objective and flexible deep learning-based models for characterizing tumor microenvironment related to spatial immune distribution. Citation Format: Seungho Cook, Haenara Shin, Mi-Kyoung Seo, Dae Seung Lee, Hongyoon Choi. Deep learning-based mapping of tertiary lymphoid structure scores from H&E images of renal cell carcinoma trained by spatial transcriptomics data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5420.
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Rustamkhanov, R. A., K. Sh Gantsev, and D. S. Tursumetov. "Tertiary Lymphoid Structures and Cancer Prognosis (Brief Review)." Creative surgery and oncology 9, no. 4 (2020): 293–96. http://dx.doi.org/10.24060/2076-3093-2019-9-4-293-296.
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This brief review is devoted to the role of tertiary lymphoid structures in oncological processes. A number of research studies carried out over the past ten years have shed light on the functions of such structures in various diseases, as well as their role in the progression of the pathological process or resolution of a disease. The data presented in some research works confirms the relationship between the presence of tumour-specific (tumour-associated) tertiary lymphoid structures and a favourable prognosis in patients with various oncological diseases, which suggests the participation of tertiary lymphoid structures in effective local antitumour immune responses. However, no reliable evidence has so far been obtained that could confirm the contribution of tertiary lymphoid structures to immune processes in vivo, with the available information being largely of a correlative character. It should be emphasized that the clinical significance of tertiary lymphoid structures ranges from a destructive to protective impact, which indicates the need for an improved understanding of the structure and case-specific function of these organs before conducting clinical targeting.
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Robles, Marcel R., Michael Malkowski, and Sandeep Krishnan. "S1842 Tertiary Lymphoid Structure Mimicking Pancreatic Mass." American Journal of Gastroenterology 117, no. 10S (2022): e1285-e1286. http://dx.doi.org/10.14309/01.ajg.0000864008.96774.a4.
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Evans, Isabel, and Mi-Yeon Kim. "Involvement of lymphoid inducer cells in the development of secondary and tertiary lymphoid structure." BMB Reports 42, no. 4 (2009): 189–93. http://dx.doi.org/10.5483/bmbrep.2009.42.4.189.
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Amwas, Nour, Darya Alizadeh, Christine Brown, et al. "Abstract A038: Inducing tumor associated tertiary lymphoid structures using cellular therapy." Cancer Immunology Research 13, no. 2_Supplement (2025): A038. https://doi.org/10.1158/2326-6074.io2025-a038.
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Abstract Targeting the tumor microenvironment (TME) to be more immune permissive is a potential strategy for enhancing immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, providing a promising avenue for treating aggressive tumors such as glioblastoma multiforme (GBM). Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that arise in response to chronic inflammation and mimic the structure and function of secondary lymphoid organs. The spontaneous presence of TLS in some solid tumors, including GBM, is associated with improved clinical outcome and responsiveness to immunotherapy. I hypothesize that membrane tethered anti-LTβR Sc-Fv (mTa) T cells can function as lymphoid tissue inducer cells (LTi) and interact with lymphoid tissue organizer cells (LTo) in the TME, that express lymphotoxin-β receptor (LTβR), to nucleate TLS. To this end, we screened commercially available murine LTβR agonist antibodies to induce NFκB signaling. When a lead candidate with robust NFkB activation was injected in situ into mice orthotopically injected with a murine glioma cell line, we found multiple TLS-like lymphoid aggregates. We therefore sequenced and cloned a membrane-tethered version of this antibody alongside a CAR construct to generate mTa-CAR-T cells. mTa-CAR T cells could activate LTβR in an NFκB-GFP reporter assay. We proceeded to intratumorally inject these cells into a syngeneic mouse GBM tumor model to evaluate TLS induction and assess the ability of mTa-CAR T cells to improve antitumor efficacy and survival. This study attempts to identify strategies to remodel the TME of GBM and nucleate TLS using cellular therapy to improve the response to CAR-T therapy and survival of GBM patients. Citation Format: Nour Amwas, Darya Alizadeh, Christine Brown, Victor Chiu, Colt Egelston, Diana Gumber, Hanmin Wang, John Williams, Leo David Wang. Inducing tumor associated tertiary lymphoid structures using cellular therapy [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A038.
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Zhou, Xingwang, Wenyan Li, Jie Yang, et al. "Tertiary lymphoid structure stratifies glioma into three distinct tumor subtypes." Aging 13, no. 24 (2021): 26063–94. http://dx.doi.org/10.18632/aging.203798.
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Gorecki, Grace, Lan Gardner Coffman, Sarah E. Taylor, and Tullia C. Bruno. "Tertiary lymphoid structure prevalence and prognostic value in cervical cancer." Journal of Clinical Oncology 41, no. 16_suppl (2023): e17521-e17521. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e17521.
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e17521 Background: Recurrent or progressive cervical cancer have limited second-line treatment options. Response rates are often poor to second-line therapy (average response rate of 15%). Identification of factors which predict response to immunotherapy and targets to enhance the immune response are critically needed in cervical cancer. Chronic inflammation can initiate an immune response in non-secondary lymphoid organs (SLO) and form a Tertiary Lymphoid Structure (TLS). TLS is composed of immune cells clustered and organized and responsible for immune cell chemotaxis, which impacts cancer therapeutic response. Chemokine ligand 13 (CXCL13) is related to B cell attraction and TLS formation. Recent work from our group demonstrated human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) exhibited greater tumor infiltrating B cells (TIL-Bs) and TLS vs HPV negative disease indicating a role for viral infection in immune infiltration. Most cervical cancer is caused by HPV infection, therefore we investigated prognostic significance of immune infiltration in cervix cancer. Methods: A cohort analysis was conducted on 43 patients diagnosed with early stage cervical cancer. The presence of B cells, CD8 T cells, and CXCL13 was analyzed using singleplex immunohistochemistry staining. We separated infiltration into high infiltration and low infiltration, defined by their median value. TLS was identified using a multiplex immunofluorescence for TLS maturity panel. Histological findings were associated with cohort data. Results: High intratumoral infiltration of CD8 T cells was associated with longer overall survival in cancer patients. Median survival was 45 months for low infiltration group, whereas it was not reached by higher T cell infiltration (p < 0.05). The prognostic value of T cell infiltration was stronger in adenocarcinoma, typically associated with worse outcomes, than in squamous cell carcinoma. In adenocarcinoma, median survival was 58 months for low T cell infiltration, it was not reached by high infiltration group. CXCL13 levels were prognostic for recurrence-free survival, with median survival of 53 months in low expression group and not reached in high CXCL13 presence group (p < 0.05). The presence of TLS compared to low B cell infiltration was associated to higher survival, with 0% of deaths in the TLS group vs 40% in low B cell infiltration. While there was no correlation between TIL-B and patient outcomes, the presence of B cells in the aggregation process and higher CXCL13 levels were associated with improved survival, with 9% deaths vs 36% in low B cell group, possibly due to the support of TLS formation by B cell aggregation surrounded by CXCL13. Conclusions: Our study suggests that the presence of TLS, whether forming or established, is linked to improved clinical outcomes in cervical cancer. Further research is necessary to investigate the response of this cancer type to immunotherapy.
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Sunyer, J. Oriol, Yasuhiro Shibasali, Fumio Takizawa, Ding Yang, Pierre Boudinot, and Aleksei Krasnov. "IDENTIFICATION OF PRIMORDIAL ORGANIZED LYMPHOID STRUCTURE IN THE SPLEEN OF TELEOST FISH." Journal of Immunology 204, no. 1_Supplement (2020): 92.40. http://dx.doi.org/10.4049/jimmunol.204.supp.92.40.
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Abstract Induction of adaptive immune responses in higher vertebrate species occur within organized lymphoid structures (e.g. lymph nodes, Peyer’s patches). It has been proposed that such structures emerged throughout evolutionary time with the goal to maximize encounters between antigens, antigens-presenting cells and B-T lymphocytes. Fish lack such structures and thus, it remains unknown how and where antigen-specific immunoglobulin responses are induced in these species. To understand how systemic immune responses are induced in teleost lymphoid organs, Rainbow Trout were immunized with several soluble protein antigens. Overall, our results identified the spleen as the major site for CD4+ T and IgM+ B cell proliferation in systemic lymphoid organs upon immunization. The proliferating splenic IgM+ B cells were frequently observed as clusters in the vicinity of melano-macrophage centers. Moreover, in these areas we observed aggregates of B and T lymphocytes with a loose organized structure reminiscent of the cellular architecture frequently associated with tertiary lymphoid organs. Laser dissection microdissection of these areas enabled us to evaluating the immunoglobulin IgM repertoires within these structures upon immunization. Critically, repertoire analysis identified processes of antigen-specific B cell clonal expansion. In conclusion, these data points to the previously unrecognized existence of primordial semi-organized lymphoid tissue in the spleen of teleost fish in which adaptive IgM immune responses are induced. Our findings provide strong evidence that the induction of antigen-specific immune responses in all bony vertebrates requires the formation of organized or semi-organized lymphoid structures.
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Denton, Alice E., Silvia Innocentin, Edward J. Carr, et al. "Type I interferon induces CXCL13 to support ectopic germinal center formation." Journal of Experimental Medicine 216, no. 3 (2019): 621–37. http://dx.doi.org/10.1084/jem.20181216.
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Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection–induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.
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van der Leun, Anne M. "Tertiary lymphoid structure formation: A matter of tumor-immune co-evolution." Molecular Immunology 175 (November 2024): 143–45. http://dx.doi.org/10.1016/j.molimm.2024.09.012.
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HAYASE, SHIMON, NORIKATSU MIYOSHI, SHIKI FUJINO, et al. "Fibroblast Activation Protein and Tertiary Lymphoid Structure in Colorectal Cancer Recurrence." Anticancer Research 42, no. 12 (2022): 5897–907. http://dx.doi.org/10.21873/anticanres.16099.
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Briem, Oscar, Eva Källberg, Siker Kimbung, et al. "CD169+ Macrophages in Primary Breast Tumors Associate with Tertiary Lymphoid Structures, Tregs and a Worse Prognosis for Patients with Advanced Breast Cancer." Cancers 15, no. 4 (2023): 1262. http://dx.doi.org/10.3390/cancers15041262.
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The presence of CD169+ macrophages in the draining lymph nodes of cancer patients is, for unknown reasons, associated with a beneficial prognosis. We here investigated the prognostic impact of tumor-infiltrating CD169+ macrophages in primary tumors (PTs) and their spatial relation to tumor-infiltrating B and T cells. Using two breast cancer patient cohorts, we show that CD169+ macrophages were spatially associated with the presence of B and T cell tertiary lymphoid-like structures (TLLSs) in both PTs and lymph node metastases (LNMs). While co-infiltration of CD169+/TLLS in PTs correlated with a worse prognosis, the opposite was found when present in LNMs. RNA sequencing of breast tumors further confirmed that SIGLEC1 (CD169) expression was associated with mature tertiary lymphoid structure (TLS), and Treg and Breg signatures. We propose that the negative prognostic value related to CD169+ macrophages in PTs is a consequence of an immunosuppressive tumor environment rich in TLSs, Tregs and Bregs.
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Erlich, Emma, Rafael Czepielewski, Shashi Kumar, et al. "B cells drive tertiary lymphoid organ formation in ileal inflammation." Journal of Immunology 208, no. 1_Supplement (2022): 113.18. http://dx.doi.org/10.4049/jimmunol.208.supp.113.18.
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Abstract Crohn’s disease [CD] is one of the two most common forms of inflammatory bowel disease, affecting over half a million Americans. Like many other diseases with chronic inflammation, some patients with CD develop tertiary lymphoid organs [TLO] in areas of the gastrointestinal tract with active disease. TLOs are organized clusters of lymphocytes, similar in structure to secondary lymphoid organs, though they develop after birth and their contribution to pathogenesis in CD, or other diseases, is unclear. We, and others, have also found B cell rich lymphoid aggregates in the mesenteric fat of CD patients along dramatically remodeled lymphatic vessels. TNFΔARE/+ is a murine model of ileal inflammation that recapitulates several key features of ileal CD, including development of mesenteric tertiary lymphoid organs. Use of this model revealed that mesenteric TLOs block cellular and molecular export from the gut, leading us to wonder if mechanisms that interfere with their development might reduce ileitis. TNFΔARE/+ mice that lack B cells revealed that B cells are required for tertiary lymphoid organ formation in this model. Without these TLOs, lymphatic outflow from the intestine was restored. Nonetheless, histological and flow cytometric approaches reveal no difference in local inflammation in the ileum. However, systemic inflammation, as assessed by metabolic cages and changes in body weight over time, increased. This suggests that TLOs may act to trap inflammatory signals locally, preventing systemic dissemination of inflammatory cells or mediators. Work supported by NIH grants DP1-DK109668-04 and T32-DK077653-27 and the Kenneth Rainin Foundation
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Tang, Weilong, Chaiyaporn Kuwentrai, Matthew J. Webber, Zhou Ye, and Jiandong Huang. "Abstract 862: Dynamic hydrogel drug delivery systems for enhancing tertiary lymphoid structure formation and maturation." Cancer Research 85, no. 8_Supplement_1 (2025): 862. https://doi.org/10.1158/1538-7445.am2025-862.
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Introduction: Tertiary lymphoid structures (TLSs), also known as ectopic lymphoid structures, are organized lymphoid-like aggregates that can form within the tumor microenvironment. TLSs exhibit similar structural and functional characteristics to secondary lymphoid organs, such as lymph nodes, and are associated with improved cancer prognosis and enhanced immune responses, including immune checkpoint blockade (ICB) therapies. However, inducing mature TLSs remains a significant challenge. Our study aims to develop a dynamic hydrogel drug delivery system that stimulates the formation and maturation of TLSs. Design: The study involved the synthesis of a hydrogel through supramolecular interactions between 4-(4-chlorophenyl)pyridine-modified hyaluronic acid (HA-CPP) and cucurbit[8]uril (CB[8]). The hydrogel was loaded with the cytokines CXCL13 and LIGHT or with liposomes encapsulating the mRNA coding for these two cytokines, and was injected into cancer-bearing mouse models. We assessed the effect of the hydrogel on TLS formation and maturation through immunofluorescence staining. We also investigated tumor growth and survival rates. Furthermore, we explored the combined effect of the hydrogel and anti-PD1 ICB therapy on tumor suppression and TLS formation. Results and discussion: The study demonstrated that a single injection of the HA-CPP⸦CB[8] hydrogel containing CXCL13 and LIGHT effectively increased TLS density, facilitated TLS maturation, suppressed tumor growth, and extended survival in the intraperitoneal melanoma mouse model. Moreover, the combination of the hydrogel-based drug formulation and anti-PD1 ICB therapy resulted in increased tumor suppression, improved survival rates, and further strengthened TLS formation. Furthermore, although TLS formation in some solid tumor locations like subcutaneous areas was significantly suppressed compared to that in intraperitoneal areas, our mRNA-loaded hydrogel still effectively induced TLS and combated tumors in various subcutaneous tumor models, including melanoma, breast cancer, colon cancer, and pancreatic cancer. This effectiveness is likely due to the adaptability, high translational efficiency, and durable bioactivity of mRNA therapies. Conclusion: The study concludes that the HA-CPP⸦CB[8] hydrogel-based drug formulation acts as an effective synthetic immune niche scaffold for promoting mature TLS formation within tumors. This approach provides a promising strategy for advancing tumor immunotherapy by enhancing the immune response against various cancers and improving the efficacy of ICB therapy. Citation Format: Weilong Tang, Chaiyaporn Kuwentrai, Matthew J. Webber, Zhou Ye, Jiandong Huang. Dynamic hydrogel drug delivery systems for enhancing tertiary lymphoid structure formation and maturation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 862.
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Zou, Ji’an, Yingzhe Zhang, Yue Zeng, et al. "Tertiary Lymphoid Structures: A Potential Biomarker for Anti-Cancer Therapy." Cancers 14, no. 23 (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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Jiang, Quan, Chenyu Tian, Hao Wu, et al. "Tertiary lymphoid structure patterns predicted anti-PD1 therapeutic responses in gastric cancer." Chinese Journal of Cancer Research 34, no. 3 (2022): 365–82. http://dx.doi.org/10.21147/j.issn.1000-9604.2022.04.05.
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Nayar, Saba, Joana Campos, Charlotte G. Smith, et al. "Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology." Proceedings of the National Academy of Sciences 116, no. 27 (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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Hill, David G., Liang Yu, Hugh Gao, et al. "Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development." International Journal of Cancer 143, no. 1 (2018): 167–78. http://dx.doi.org/10.1002/ijc.31298.
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Gonzalez, Ricardo A. Chaurio, Kyle K. Payne, Carmen Maria Anadon Galindo, et al. "Satb1 deficiency licenses TFH-differentiation and Tertiary Lymphoid Structure formation in cancer." Journal of Immunology 204, no. 1_Supplement (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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Ichii, Osamu, Marina Hosotani, Md Abdul Masum, et al. "Close Association between Altered Urine–Urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis during Nephritis." Journal of the American Society of Nephrology 33, no. 1 (2021): 88–107. http://dx.doi.org/10.1681/asn.2021040575.
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BackgroundKidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear.MethodsRPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures.ResultsRegardless of infection, TLSs in the RP, termed urinary tract–associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-γ as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-γ, TNF-α) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-α/FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development.ConclusionsTLS formation in the RP is possible and altered urine–urothelium barrier–based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.
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Adoke, Kasimu, and Sanusi Haruna. "10 Tertiary lymphoid structure in pancreatic ductal adenocarcinoma; a potential target in an immunologically inert malignancy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (2021): A10. http://dx.doi.org/10.1136/jitc-2021-sitc2021.010.
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BackgroundTertiary lymphoid structure (TLS) are immune aggregates with various degrees of organization that forms outside of secondary lymphoid organ in response to chronic inflammation, infection or tumours.1 2 TLS like secondary lymphoid organ, has defined T cell zones, B cell zones, high endothelial venules (HEV) and matured dendritic cells. They have been shown to correlate with increase patient survival in many tumours. Pancreatic ductal carcinoma (PDAC) is generally believed to be immunologically inert, low tumour mutation burden (TMB) and poor response to checkpoint blockade. Recent findings in some patients with PDAC shows significant intratumoral cytotoxic T cell infiltration and a high Inflammatory signature. Since current immunotherapy aim to enhance CD 8+ T cells, we aim to investigate the contribution of humoral immunity in patients with TLS in PDAC.MethodsTissue blocks were obtained from departmental archive and sections were cut and stained with routine H&E of all patients who underwent surgery for pancreatic cancer from 2015–2021 at Federal Medical Centre Birnin Kebbi. Serial sections were done at 5µ and four immunohistochemical stains CD 3, CD8, CD20 and PD-L1 were used. Statistical analysis was done using spss version 24.ResultsA total of nine cases of PDAC were diagnosed during the period with a Male Female ratio of 1:1.25 with an age range of 40–68 years and a mean age of 57.7±8.4. Five cases (55.6%) of PDAC showed TLS with marked expression of CD20 B+ cells seen in all five cases (figures 1 and 2). Also expressed are CD 8+ cytotoxic T cells and PD-L1. Prognosis was better in patients with TLS compare with those without TLS.Abstract 10 Figure 1TLS in pancreatic ductal adenocarcinoma.Abstract 10 Figure 2CD 20 stain in TLSConclusionsTLS can be a potential therapeutic target to explore in the future for treatment of some cancers including PDAC through induction of TLS formation in inert tumours or B lymphocyte specific target.ReferencesPitzalis C, Jones GW, Bombardieri M, Jones S. Ectopic lymphoid like structures in infection, cancer and autoimmunity. Nat Rev Immunol 2014; 14: 447–462.Neyt K, Perros F, Geurtsvan C, Hammad H. Lambrecht B. Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol 2012; 33: 297–305.Ethics ApprovalEthical Approval was obtained for this study with Ethics number KSHREC Registration Number:104:6/2019ConsentN/A
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Daya, Khodor Abou, Daqiang Zhao, Kyle Biery, and Martin H. Oberbarnscheidt. "Tertiary lymphoid organs in renal chronic allograft rejection." Journal of Immunology 204, no. 1_Supplement (2020): 161.14. http://dx.doi.org/10.4049/jimmunol.204.supp.161.14.
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Abstract Chronic allograft rejection remains a major obstacle to long-term allograft survival. The immunologic role of tertiary lymphoid organs (TLO) in allograft rejection is unclear. Here, we employed a chronic renal allograft rejection model in mice and intravital 2-photon microscopy to investigate the function of TLO in transplant rejection. CB6F1 (F1) RIP-LTα (preformed TLO) or F1 (no TLO) kidney grafts were transplanted to WT B6 recipients and survival monitored. To investigate immunologic function of TLO, we adoptively transferred B6-RIPLTα CD11c-YFP mice with 10m naïve dsRed OT-I T cells or 10m CTR-labeled NP-specific B cells + 10m CFP+ OT-II cells and immunized with NP-OVA + alum. Intravital 2P imaging of renal TLO was performed at time points 0, 3, 6, 24 or 72 hours after immunization. 4D image analysis was performed and mean speed, displacement, arrest coefficient (AC) and contact times (CT) with DC were calculated for OT-I, OT-II and NP-B cells. F1 RIP-LTα grafts rejected significantly faster (MST= 54) than F1 grafts (MST= 225), demonstrating that TLO contribute to allograft rejection. F1 RIP-LTα grafts contained similar numbers of, but larger TLO than F1 grafts as demonstrated by histology. Mean speed and displacement of OT-I and OT-II cells significantly decreased over time after immunization while AC and mean CT significantly increased. B cell mean speed, displacement and AC increased after immunization. These data are consistent with B cell activation and productive T cell-DC interactions and mirror previously reported data in secondary lymphoid organs. We provide first evidence that TLO provide a local structure for T and B cell activation that propagates anti-graft immune responses in the setting of chronic rejection.
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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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Yamamoto, Shinya, and Motoko Yanagita. "A Novel Pathological Mechanism of Tertiary Lymphoid Structure Formation in the Renal Pelvis." Journal of the American Society of Nephrology 33, no. 1 (2021): 4–6. http://dx.doi.org/10.1681/asn.2021111465.
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Wang, Jin, Dongbo Jiang, Xiaoqi Zheng, et al. "Tertiary lymphoid structure and decreased CD8+ T cell infiltration in minimally invasive adenocarcinoma." iScience 25, no. 3 (2022): 103883. http://dx.doi.org/10.1016/j.isci.2022.103883.
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雷, 鑫焌. "Research Progress of Tertiary Lymphoid Structure and Tumor-Associated Macrophages in Hepatocellular Carcinoma." Advances in Clinical Medicine 12, no. 02 (2022): 1067–73. http://dx.doi.org/10.12677/acm.2022.122157.
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Schroeder, A., F. Zhu, and H. Hu. "LB867 Development of tertiary lymphoid structure in dermal tumors and anti-tumor immunity." Journal of Investigative Dermatology 144, no. 8 (2024): S151. http://dx.doi.org/10.1016/j.jid.2024.06.1247.
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Boulat, Victoire, Elena Alberts, Carin Andrea Brundin, Dinis P. Calado, and Anita Grigoriadis. "Abstract 1375: Active inhibition of chemokine-mediated migration impairs tertiary lymphoid structure formation." Cancer Research 85, no. 8_Supplement_1 (2025): 1375. https://doi.org/10.1158/1538-7445.am2025-1375.
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Abstract The presence of tumor-infiltrating B cells (TIL-B) and tertiary lymphoid structures (TLS) in the primary tumor microenvironment carries prognostic value across cancer types. We have shown that triple-negative breast cancer (TNBC) patients with robust germinal center (GC) responses in their lymph nodes (LN) exhibit higher levels of TILs and more TLS. In this study, we investigated human and mouse immune-cold TNBCs to uncover mechanisms by which tumor-LN crosstalk may be impaired. In orthotopic TNBC mouse models, we observed robust GC responses in tumor-draining LNs. However, minimal TIL-Bs and no TLS were detected in the primary tumors. The tumor-draining LNs were confirmed as the source of the few TIL-B by using FTY720, a drug that blocks LN exit. Transcriptomic analysis of 124 untreated TNBC patients confirmed a strong association between TIL-B/TLS presence and chemokine-enriched pathways. Notably, in orthotopic TNBC mouse models, multiplex proteomic analyses of the tumor secretome revealed that most TIL-B- and TLS-associated chemokines were absent. Next, we conducted ex vivo migration assays and found unexpectedly that supplementing mouse tumor-conditioned medium with chemokines induced significantly less migration compared to chemokine-supplemented culture medium. In vivo, co-injection of genetically engineered chemokine-expressing cancer-associated fibroblasts (CAFs) did not elicit TLS formation nor increased TIL-B infiltration in the primary tumors. These findings suggest the presence of specific inhibitory factors within the tumor secretome that impair chemokine-mediated migration and immune cell infiltration. Using molecular weight-based fractionation and high-throughput analysis, we are narrowing down the identity of these components and conducting functional studies to validate their effects. Preliminary experiments show that removing these factors can restore chemokine activity, permitting B cell migration. In vivo, we are evaluating the combination of genetically engineered chemokine-expressing CAFs and systemic inhibition of these factors to promote TIL-B infiltration and TLS formation. Preliminary data indicate this dual treatment promotes the formation of large peritumoral B cell aggregates, providing critical insights into the factors enabling tumor immune infiltration and organization. Ongoing human transcriptomic analyses on internal and publicly available datasets support a strong association between chemokine expression, reduced inhibitory factor secretion, and TIL-B presence across human cancer types, including TNBC, colon and lung cancer. This work defines that the absence of TIL-B and TLS in cancer is the consequence of a combination of mechanisms: insufficient chemokine production by the tumor microenvironment to drive immune infiltration from the LN, coupled with the active secretion of factors that impair chemokine functionality. Citation Format: Victoire Boulat, Elena Alberts, Carin Andrea Brundin, Dinis P. Calado, Anita Grigoriadis. Active inhibition of chemokine-mediated migration impairs tertiary lymphoid structure formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1375.
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Ota, Yosuke, Kimiya Matsuda, Hiroki Umehara, and Hitoshi Ban. "Abstract LB125: Increased expression of tertiary lymphoid structure related genes contributes the strong anti-tumor activity of 5DEX-0509R that is dextran conjugated TLR7 agonist targeting TAM." Cancer Research 85, no. 8_Supplement_2 (2025): LB125. https://doi.org/10.1158/1538-7445.am2025-lb125.
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Abstract Introduction: Toll-like Receptors (TLRs) are a class of Pattern Recognition Receptors (PRRs) capable of recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Since TLR activation in the tumor initiates anti-tumor immune responses, TLR agonists are an attractive target and are still actively studied in cancer immunotherapy. We have reported that 5DEX-0509R, a TLR7 agonist targeting Tumor-Associated Macrophages (TAMs), demonstrates selective delivery to TAMs and strongly shifts their phenotype from M2-like to M1-like, resulting in anti-tumor efficacy in various mouse models. Tertiary Lymphoid Structures (TLSs) are the lymph node-like structures in non-lymphoid tissue and are known to be predictive markers for cancer immunotherapy. TLSs in the tumor are formed by the interaction between Lymphoid Tissue Inducer (Lti) cells, High Endothelial Venules (HEVs), stroma, Follicular Helper T (Tfh) cells, and B cells. M1-like macrophages are reported to be one of the Lti cell populations. In this study, we explored the involvement of tertiary lymphoid structure formation in the anti-tumor activity of 5DEX-0509R. Methods: To clarify the effect of 5DEX-0509R on the tumor immune microenvironment, we analyzed the gene expression in mouse tumors by RNA sequencing. We then focused on genes related to the formation of TLSs. TLSs in the tumor ultimately support plasma cell maturation, which expresses antibodies against tumor antigens. Next, we evaluated the anti-tumor activity of 5DEX-0509R in a lymphoid cell-depleted condition using a mouse model. Results: 5DEX-0509R increased the expression of Cxcl12, Cxcl13, Ccl19, Icam1, Vcam1, Il21, Lta, and Ltb in EMT6 tumors. Cxcl13 is reported to induce Lti cell and HEV formation. Vcam, Icam, and Ccl19 are reported to be expressed on HEVs. Lta and Ltb are reported to be important inducers of TLSs. Il21 is known to be secreted by Tfh cells. Additionally, dosing of 5DEX-0509R increased the number of CD19+ B cells in the tumor, as shown by IHC analysis. These data suggest that 5DEX-0509R administration may induce the early formation of TLSs in the tumor microenvironment. In a tumor model using nude mice, the anti-tumor activity of 5DEX-0509R was attenuated. Furthermore, CD19 depletion in a mouse tumor model attenuated the anti-tumor activity of 5DEX-0509R. These data suggest that B cells are involved in the anti-tumor activity of 5DEX-0509R. Conclusion: These data suggest that the strong polarization of TAMs into an M1-like phenotype by 5DEX-0509R triggers the change of the tumor immune microenvironment towards the formation of early TLSs. Furthermore, B cells in the tumor contribute to the anti-tumor activity of 5DEX-0509R. We believe our 5DEX-0509R would be a novel treatment option for cancer patients. Citation Format: Yosuke Ota, Kimiya Matsuda, Hiroki Umehara, Hitoshi Ban. Increased expression of tertiary lymphoid structure related genes contributes the strong anti-tumor activity of 5DEX-0509R that is dextran conjugated TLR7 agonist targeting TAM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB125.
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Yang, Haihua, Kuifei Chen, Yinan Meng, et al. "Review: radiotherapy-mediated B cells within the TLS influence the tumor microenvironment." Journal for ImmunoTherapy of Cancer 13, no. 7 (2025): e011617. https://doi.org/10.1136/jitc-2025-011617.
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The tumor microenvironment (TME) is a diverse and intricate structure consisting of tumor cells, stromal cells, endothelial cells, and immune cells. It is characterized by the communication between tumor cells and both innate and adaptive immune cells. Tertiary lymphoid structures (TLS) are temporary abnormal collections of lymphoid tissues in which specialized immune responses against tumors can occur. B cells are crucial for the prognostic prediction of various cancers, particularly in response to immunotherapy. There are many types of B cells within the TME, including naive, terminally differentiated plasma, and memory B cells. Our focus was to understand the various types of B cells and how radiation therapy influences B cells in TLS. In this review, we discuss the notion that radiotherapy may alter the creation and function of B cells in TLS, which could result in a powerful and advanced form of cancer immunity.
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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 (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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Cho, Kyung Serk, Jiahui Jiang, Daiwei Zhang, et al. "Abstract 7424: iStarTLS: Advanced detection and phenotyping of tertiary lymphoid structures." Cancer Research 84, no. 6_Supplement (2024): 7424. http://dx.doi.org/10.1158/1538-7445.am2024-7424.
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Abstract Tertiary lymphoid structures (TLSs) are clusters of immune cells formed in non-lymphoid tissues. They are often found at sites of chronic inflammation, notably within the invasive margins and the core of various solid tumors. TLSs are pivotal in mediating anti-tumor immunity. However, our understanding of TLSs in large/complex tissue contexts remains incomplete due to the lack of computational tools to effectively detect and phenotype TLSs. Recent advances in spatially resolved transcriptomics (SRT) present a broader spectrum of analytical possibilities for investigating the spatial phenotypic heterogeneity of TLSs and their interaction with stromal and cancer cells. Here, we present iStarTLS (Inferring Super-resolution Tissue ARchitecture for TLSs), a computational toolkit designed to process SRT data for TLS detection and phenotyping and showcase its performance on breast, bladder, and lung cancer samples. By effectively integrating spatial gene expression data with state-of-the-art machine learning techniques, we can substantially enhance our capabilities in TLS detection and comprehensive phenotyping. iStarTLS starts by enhancing the spatial resolution of spot-level gene expression data to near-single-cell resolution by leveraging high-resolution information provided by paired histology images. To detect TLSs and infer their cellular composition, we developed a TLS signature. Based on the high-resolution gene expression measurements and a curated reference panel of cell type-specific markers, we score cell type-specific gene signatures to obtain a cell type probability map across the whole tissue section. This map gives rise to a segmentation of key cell type components of TLSs, enabling the spatial mapping and colocalization of different cell types. Moreover, such an approach would allow us to infer the phenotypic states of cells within the TLSs, assess their cellular compositions, and discern their cellular organization in large, spatially heterogeneous tissues at a near-single-cell resolution. Notably, in conjunction with nuclei segmentation of high-resolution histology images, iStarTLS precisely maps high endothelial venules (HEVs), a key structure within TLSs often overlooked by previous studies. iStarTLS paves the way for uncovering novel mechanisms of immune-tumor interactions and designing personalized therapies targeting specific cellular components or states within TLSs. Citation Format: Kyung Serk Cho, Jiahui Jiang, Daiwei Zhang, Yunhe Liu, Jianfeng Chen, Rossana L. Segura, Xinmiao Yan, Guangsheng Pei, Luisa M. Soto, Yanshuo Chu, Ansam F. Sinjab, Cassian Yee, Scott Kopetz, Anirban Maitra, Andrew Futreal, Alexander Lazar, Amir A. Jazaeri, Humam Kadara, Jianjun Gao, Mingyao Li, Linghua Wang. iStarTLS: Advanced detection and phenotyping of tertiary lymphoid structures [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 7424.
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Zhao, Zhan, Hui Ding, Zheng-bin Lin, et al. "Relationship between Tertiary Lymphoid Structure and the Prognosis and Clinicopathologic Characteristics in Solid Tumors." International Journal of Medical Sciences 18, no. 11 (2021): 2327–38. http://dx.doi.org/10.7150/ijms.56347.
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Lynch, Kevin T., Samuel J. Young, Max O. Meneveau, et al. "Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma." Journal for ImmunoTherapy of Cancer 9, no. 6 (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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Buisseret, Laurence, Christine Desmedt, Soizic Garaud, et al. "Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer." Modern Pathology 30, no. 9 (2017): 1204–12. http://dx.doi.org/10.1038/modpathol.2017.43.
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Tao, Ping, Zhenyu Wang, Jiongyuan Wang, et al. "Integrated multi-omics analysis reveals immune landscape of tertiary lymphoid structure in retroperitoneal liposarcoma." Journal of Clinical Oncology 42, no. 16_suppl (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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He, Miao, Qihua He, Xiuyu Cai, et al. "Intratumoral tertiary lymphoid structure (TLS) maturation is influenced by draining lymph nodes of lung cancer." Journal for ImmunoTherapy of Cancer 11, no. 4 (2023): e005539. http://dx.doi.org/10.1136/jitc-2022-005539.
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BackgroundTertiary lymphoid structure (TLS) is an organized infiltration of immune cells, showing features of germinal center (GC) commonly seen in secondary lymphoid organs. However, its relationship with tumor-draining lymph nodes (TDLNs) has not been studied and we hypothesized that TDLN may influence maturation of intratumoral TLS in non-small cell lung cancer (NSCLC).MethodsTissue slides of 616 patients that had undergone surgeries were examined. Cox proportional hazard regression model was used to assess risk factors of patients’ survival, and logistic regression model was used for their relationship with TLS. Single-cell RNA-sequencing (scRNA-seq) was employed to explore transcriptomic features of TDLNs. Immunohistochemistry, multiplex immunofluorescence and flow cytometry were performed to analyze cellular composition. Cellular components of NSCLC samples from The Cancer Genome Atlas database were inferred with Microenvironment Cell Populations-counter (MCP-counter) method. Murine NSCLC models were used to dissect underlying mechanisms for relationship between TDLN and TLS maturation.ResultsWhile GC+TLS was associated with better prognosis, GC−TLS was not. TDLN metastasis reduced the prognostic relevance of TLS, and was associated with less GC formation. Primary tumor sites showed reduced B cell infiltration in TDLN-positive patients, and scRNA-seq revealed diminished memory B cell formation in tumor-invaded TDLNs, together with an emphasis on weakened interferon (IFN)-γ response. Murine NSCLC models revealed that IFN-γ signaling is involved in memory B cell differentiation in TDLNs and GC formation in primary tumors.ConclusionsOur research emphasizes the influence of TDLN on intratumoral TLS maturation and suggests a role of memory B cells and IFN-γ signaling in this communication.
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Chung, Shin-Yi, Ming-Huang Chen, Yi-Chen Yeh, Yu-Chan Chang, and Yu-Cha Wang. "Abstract 1527: Exploring the role of tertiary lymphoid structure in the tumor microenvironment of cholangiocarcinoma." Cancer Research 84, no. 6_Supplement (2024): 1527. http://dx.doi.org/10.1158/1538-7445.am2024-1527.
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Abstract Cholangiocarcinoma is the second most common hepatobiliary malignant tumor besides liver cancer, grows from bile duct epithelial cells. However, surgery is the only hope for most patients with cholangiocarcinoma, but the effectiveness of treatment is not outstanding. Even though other methods of treatment, such as chemotherapy and radiation therapy, have limited effects. The immunotherapy and precision treatment have become the latest expectations of patients. Here, we analyzed the TCGA and GEO database to classify the cold and hot tumor using hierarchical clustering. The MCP counter results demonstrated that two genes, MS4A1 and CD79A, could identify the hot and cold tumor subgroups after TCGA data training and similar results show in GEO database. We also performed the tissue array for 105 cholangiocarcinoma tissue samples and found patients with high expression levels of MS4A1 or CD79A have better disease free survival (DFS) and progression free survival (PFS) (p value =0.0131 and 0.0017). In addition, we tested the tertiary lymphoid structures (TLS) signatures in tissue array sections, which is associated with the present of MS4A1 and CD79A. The results shows that patients who received the immunotherapy with TLS signatures have longer overall survival (OS) and PFS (p value =0.017 and 0.006). Collectively, B cell lineages or TLS could be an ideal biomarker to lead the clinical treatment and wish can broader applications in other diseases. Citation Format: Shin-Yi Chung, Ming-Huang Chen, Yi-Chen Yeh, Yu-Chan Chang, Yu-Cha Wang. Exploring the role of tertiary lymphoid structure in the tumor microenvironment of cholangiocarcinoma [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 1527.
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Gomez Medellin, Jorge E., Maile Kananiokala Hollinger, Jillian Rosenberg, et al. "VEGFR3-driven pulmonary lymphangiogenesis exacerbates induction of bronchus-associated lymphoid tissue in allergic airway disease." Journal of Immunology 208, no. 1_Supplement (2022): 109.24. http://dx.doi.org/10.4049/jimmunol.208.supp.109.24.
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Abstract Asthmatic lung samples present with both a higher density of pulmonary lymphatic vessels and a higher incidence of bronchus associated lymphoid tissue (BALT). Here, we asked whether lymphangiogenesis, stimulated by the VEGF-C/VEGFR-3 signaling axis in lymphatic endothelial cells (LECs), plays a role in promoting BALT in mouse models of allergy. First, we determined that chronic intratracheal instillation of house dust mite (HDM), a clinically relevant allergen, recapitulates both lymphangiogenesis and BALT induction. Intratracheal stimulation of VEGFR-3 in LECs exacerbated BALT, while blocking VEGFR-3 signaling reduced BALT. Furthermore, in transgenic mice with an expanded pulmonary lymphatic network (induced prior to allergen challenge), we found an exacerbated BALT response upon chronic HDM inhalation. Recent studies have determined that LEC-derived CXCL13 plays an important role in secondary lymphoid structure organogenesis, and thus we pondered whether LEC-derived CXCL13 could play a role in the development of tertiary lymphoid structures. Indeed, we observed an increase in lung infiltration by CXCR5+ cells when we used VEGF-C to modulate the chronic allergic response. Finally, we found that the VEGF-C exacerbated BALT phenomenon was indeed CXCL13 dependent. Altogether, these results suggest a causative role for pulmonary lymphatics in mediating BALT induction in chronic allergic airway inflammation.
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Hou, Yue, Sijing Qiao, Miao Li, et al. "The gene signature of tertiary lymphoid structures within ovarian cancer predicts the prognosis and immunotherapy benefit." Frontiers in Genetics 13 (January 10, 2023). http://dx.doi.org/10.3389/fgene.2022.1090640.
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Ovarian cancer (OC) has the lowest survival rate among gynecologic malignancies. Ectopic lymphocyte aggregates, namely tertiary lymphoid structures (TLSs), have been reported as positive biomarkers for tumor prognosis. However, the related gene signature of tertiary lymphoid structure in ovarian cancer was less understood. Therefore, this study first exhibited the organizational patterns of tertiary lymphoid structure by H&amp;E staining and immunohistochemistry (IHC), and confirmed the improved survival values of tertiary lymphoid structure and quantified tumor-infiltrating lymphocytes (CD20+ B cells and CD8+ T cells) in ovarian cancer patients. Secondly, we collected the genes involved in tertiary lymphoid structure from databases. By the univariate regression analysis, the tertiary lymphoid structure gene signature (CETP, CCR7, SELL, LAMP3, CCL19, CXCL9, CXCL10, CXCL11, and CXCL13) with prognostic value, characteristically of ovarian cancer, was constructed in the TCGA dataset and validated in the GSE140082 dataset. Thirdly, by performing CIBERSORT and Tumor Immune Dysfunction and Exclusion (TIDE) analysis, we found that the high expression of this gene signature was positively correlated with developed immune infiltration and reduced immune escape. The improved IPS score and application in the IMvigor210 dataset received PD-L1 proved the predictive value of immunotherapy for this gene signature. Furthermore, this signature showed a better correlation between tumor mutation burden and classical checkpoint genes. In conclusion, Tertiary lymphoid structure plays important role in tumor immunity and the gene signature can be evaluated as a biomarker for predicting prognosis and guiding immunotherapy in ovarian cancer.
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Palmer, Mitchell V., Douglas E. Jones, Nicholas J. Bockenstedt, and Paola M. Boggiatto. "Tertiary lymphoid structures in pulmonary granulomas of cattle experimentally infected with aerosolized Mycobacterium bovis." BMC Veterinary Research 21, no. 1 (2025). https://doi.org/10.1186/s12917-025-04804-x.
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Abstract Mycobacterium bovis is the primary cause of tuberculosis in animals, most notably cattle. In cattle and other susceptible hosts, the hallmark lesion of tuberculosis is the granuloma. Granulomas represent the host–pathogen interface where disease outcome is determined; therefore, it is critical to understand host–pathogen interactions at the granuloma level. Granulomas are highly structured lesions with distinct cellular compartments for T cells, macrophages, multinucleated giant cells, and B cells. A recognized but poorly understood morphologic feature of many granulomas is the presence of structures resembling follicular or germinal center-like arrangements of B cells known as tertiary lymphoid organs, or tertiary lymphoid structures. Pulmonary granulomas from cattle experimentally infected with M. bovis were collected at 15-, 30-, 90-, 180- and 270-days post-infection and examined for the presence of tertiary lymphoid-like structures. Follicle-like structures associated with granulomas were first seen 90 days after infection and persisted in later time points. Compartmentalization of T cells and B cells similar to follicles in germinal centers of lymph nodes was demonstrated using in situ hybridization. Additionally, the presence and arrangement of myeloid cells, endothelial cells, T follicular helper cells, and chemokines critical to tertiary lymphoid structure formation was shown to be similar to lymph node follicles and that described for tertiary lymphoid structures in other species. This represents the first demonstration by in situ hybridization of the similarities of follicle-like structures associated with pulmonary bovine tuberculous granulomas to tertiary lymphoid structures in other species and follicles within secondary lymphoid organs such as lymph nodes.
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Nayar, Saba, Jason D. Turner, Saba Asam, et al. "Molecular and spatial analysis of tertiary lymphoid structures in Sjogren’s syndrome." Nature Communications 16, no. 1 (2025). https://doi.org/10.1038/s41467-024-54686-0.
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AbstractTertiary lymphoid structures play important roles in autoimmune and non-autoimmune conditions. While many of the molecular mechanisms involved in tertiary lymphoid structure formation have been identified, the cellular sources and temporal and spatial relationship remain unknown. Here we use combine single-cell RNA-sequencing, spatial transcriptomics and proteomics of minor salivary glands of patients with Sjogren’s disease and Sicca Syndrome, with ex-vivo functional studies to construct a cellular and spatial map of key components involved in the formation and function of tertiary lymphoid structures. We confirm the presence of a fibroblast cell state and identify a pericyte/mural cell state with potential immunological functions. The identification of cellular properties associated with these structures and the molecular and functional interactions identified by this analysis may provide key therapeutic cues for tertiary lymphoid structures associated conditions in autoimmunity and cancer.
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"Tryptophan Metabolism Regulates Tertiary Lymphoid Structure Maturation." Cancer Discovery, 2025. https://doi.org/10.1158/2159-8290.cd-rw2025-061.
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Liu, Yang, Shuang-Yan Ye, Shuai He, et al. "Single-cell and spatial transcriptome analyses reveal tertiary lymphoid structures linked to tumour progression and immunotherapy response in nasopharyngeal carcinoma." Nature Communications 15, no. 1 (2024). http://dx.doi.org/10.1038/s41467-024-52153-4.
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AbstractTertiary lymphoid structures are immune cell aggregates linked with cancer outcomes, but their interactions with tumour cell aggregates are unclear. Using nasopharyngeal carcinoma as a model, here we analyse single-cell transcriptomes of 343,829 cells from 77 biopsy and blood samples and spatially-resolved transcriptomes of 31,316 spots from 15 tumours to decipher their components and interactions with tumour cell aggregates. We identify essential cell populations in tertiary lymphoid structure, including CXCL13+ cancer-associated fibroblasts, stem-like CXCL13+CD8+ T cells, and B and T follicular helper cells. Our study shows that germinal centre reaction matures plasma cells. These plasma cells intersperse with tumour cell aggregates, promoting apoptosis of EBV-related malignant cells and enhancing immunotherapy response. CXCL13+ cancer-associated fibroblasts promote B cell adhesion and antibody production, activating CXCL13+CD8+ T cells that become exhausted in tumour cell aggregates. Tertiary lymphoid structure-related cell signatures correlate with prognosis and PD-1 blockade response, offering insights for therapeutic strategies in cancers.
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Goronzy, Jörg J., and Cornelia M. Weyand. "Perivascular Tertiary Lymphoid Structures in Autoimmune Disease." Immunological Reviews 332, no. 1 (2025). https://doi.org/10.1111/imr.70047.
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ABSTRACTImmunotherapy of autoimmune diseases has expanded substantially, yet autoimmunity remains incurable, and patients suffer from chronic destructive tissue inflammation that fails to resolve. Mechanisms underlying the endurance of autoimmune memory and the lack of exhaustion are beginning to be understood. Here, we review emerging data on how decentralization of cellular immunity contributes to persistent autoimmune responses and chronicity of autoimmune tissue inflammation. Two processes are recognized as ensuring lasting immune memory: the generation of tissue‐resident memory T cells (TRM) and the formation of tertiary lymphoid structures (TLS). TLS, lymphoid aggregates formed outside of lymphoid organs, develop under conditions of chronic immune stimulation, such as autoimmune disease, anti‐tumor immunity, and during immune aging. TLS display heterogeneity in structure and cellular composition that may determine whether they ultimately serve as protective or pathogenic elements. Recent data have implicated TLS as a critical resource in upholding autoimmune responses, emphasizing their role in harming the host. In patients with autoimmune vasculitis, adventitial TLS drives protracted autoimmune disease by housing TCF1hi CD4+ T stem cells that escape exhaustion and provide a continuous supply of pathogenic effector T cells to the disease lesions. The local production and stemness of CD4+ T cells bring resilience to autoreactive immunity, defining novel therapeutic targets in the management of autoimmune disease.
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Hein, Ashley L., Natasha Singh, and Samuel M. Cohen. "Small Intestinal Adenocarcinoma Involving a Submucosal Ectopic Lymph Node: A Case Report." International Journal of Surgical Pathology, October 19, 2023. http://dx.doi.org/10.1177/10668969231204970.
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An 83-year-old male with a 55-year history of Crohn's disease, ileocecectomy 40 years prior, and naturopathic treatment for 25 years, presented with nausea, vomiting, and abdominal pain. Computed tomography of abdomen and pelvis demonstrated partial small intestinal obstruction and a 4.4-cm solid left renal mass. After 3 months of recurrent intestinal obstruction and development of a pericolonic abscess, resection of the ileocolonic anastomosis, abscess, and partial nephrectomy were performed. Histopathology demonstrated chronic active enteritis with fistula tract formation, consistent with Crohn's disease, and moderately differentiated small intestinal adenocarcinoma extending from mucosa into subserosa. A submucosal intestinal lymph node-like structure containing adenocarcinoma demonstrated endothelial venules, open marginal and intermediate sinuses, multiple polarized germinal centers, and partial capsule, consistent with an ectopic lymph node, also called a tertiary lymphoid organ. Twenty mesenteric lymph nodes were negative for carcinoma. The renal mass was a papillary renal cell carcinoma, Stage I. Intestinal tertiary lymphoid organs form in chronic immune activation and have variable structures ranging from simple B and T cell clusters to organized groups with high endothelial venules and lymphatic vessels. Encapsulation of tertiary lymphoid organs is rare, with some sources claiming this entity is never encapsulated. To our knowledge, this is the first report of small intestinal adenocarcinoma involving a submucosal encapsulated tertiary lymphoid organ, the prognostic significance of which is uncertain. We suggest increased awareness of intestinal tertiary lymphoid organs as an entity and further studies to delineate the effect their involvement by adenocarcinoma imparts on survival.
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Zhao, Ruibo, Jinghe Zhang, Jialu Ma, et al. "cGAS-activated endothelial cell–T cell cross-talk initiates tertiary lymphoid structure formation." Science Immunology 9, no. 98 (2024). http://dx.doi.org/10.1126/sciimmunol.adk2612.
Full textAbstract:
Aberrant activation of the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels were enclosed by organized lymphoid tissues that resemble tertiary lymphoid structures (TLSs). Cell-intrinsic cGAS induction promoted up-regulation of CCR5 in CD8 + T cells and led to CCL5 production in vascular endothelial cells. Peripheral CD8 + T cells were recruited to the lungs and produced CXCL13 and interferon-γ. The latter triggered endothelial cell death, potentiated CCL5 production, and was essential for TLS establishment. Blocking CCL5 or CCR5, or depleting CD8 + T cells, impaired TLS formation. cGAS-mediated TLS formation also enhanced humoral and antitumor responses. These data demonstrate that cGAS signaling drives a specialized lymphoid structure that underlies autoimmune tissue pathology.
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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.
Full textAbstract:
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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Rochefort, Juliette, Gilles Marodon, Jean‐Luc Teillaud, and Marie‐Caroline Dieu‐Nosjean. "The Sunrise of Tertiary Lymphoid Structures in Cancer." Immunological Reviews 332, no. 1 (2025). https://doi.org/10.1111/imr.70046.
Full textAbstract:
ABSTRACTFirst considered as a negative epiphenomenon in autoimmune and inflammatory diseases, with possible deleterious consequences through the production of pathological autoantibodies and antiself T cells, tertiary lymphoid structures (TLS) have gained major scientific and clinical interest in cancer due to their association with better clinical outcomes and improved responses to immunotherapy. Studies have investigated the structure and plasticity of TLS in the context of tumors and the role of the TLS B‐cell compartment in contributing to the favorable clinical outcome of cancer patients. Identifying biomarkers that indicate the presence of TLS in tumors in a noninvasive manner could therefore represent a major advance in the diagnosis and treatment decision‐making for these patients. Also, the interplay between TLS, tumor cells, and microbiota opens new avenues for deciphering the role of microorganisms in cancer development. Their use as TLS inducers further underlines the need for continued research in this field. Moreover, emerging data have emphasized the critical role of sensory and sympathetic nerves in regulating TLS formation and function. Finally, humanized mice may serve as valuable tools for developing preclinical models to study the role of human TLS in cancer, a much‐needed goal. These different topics are discussed in the present review.
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"Disease Site Dictates Tertiary Lymphoid Structure Activity in Ovarian Cancer." Cancer Discovery, 2024. http://dx.doi.org/10.1158/2159-8290.cd-rw2024-130.
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