Статті в журналах: "Tertiary lymphoid structure"

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

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Abstract Purpose Tertiary lymphoid structures are organized aggregates of immune cells present in the tumor microenvironment (TME) in which novel targets as well as beneficial biomarkers for immunotherapy in cancer were found. Here, we have developed and validated a deep learning model by integrating H&E images of renal cell carcinoma and spatial transcriptomics data to infer spatial mapping of tertiary lymphoid structure scores in TME only using hematoxylin and eosin (H&E) images. Methods A total of 20 H&E images combined with spatial transcriptomics data of renal cell carcinoma were used to develop a model. Tertiary lymphoid structure scores can be acquired for each spot in spatial transcriptomics by geometric mean of the specific gene expression relevant to B cell, T cell, immunoglobulin, fibroblast, complement, and others. A convolutional neural network using H&E image patches as inputs was developed to predict the tertiary lymphoid structure scores from H&E-stained tissue image patches of renal cell carcinoma acquired by different patients. For the external validation, the model estimated the tertiary lymphoid structure scores from H&E-stained tissue image patches of renal cell carcinoma of The Cancer Genome Atlas (TCGA-RCC). Results The tertiary lymphoid structure scores inferred by the model using H&E image patches were significantly correlated with those derived by spatial transcriptomics data as an internal validation (r = 0.68, p < 1e-10). The mean value of the deep learning-based tertiary lymphoid structure scores estimated by the TCGA-RCC tissue images was significantly correlated with the tertiary lymphoid structure scores, T cell enrichment scores and immune cell enrichment scores estimated by bulk RNA-seq data from the corresponding TCGA data. Conclusions A deep learning model to infer spatial tertiary lymphoid structure in the tumor microenvironment using H&E images was developed. As the tertiary lymphoid structure is a key to predict responsiveness of immune checkpoint inhibitors, mapping the score only using H&E images could be clinically translated into image-based biomarkers. This approach can provide objective and flexible deep learning-based models for characterizing tumor microenvironment related to spatial immune distribution. Citation Format: Seungho Cook, Haenara Shin, Mi-Kyoung Seo, Dae Seung Lee, Hongyoon Choi. Deep learning-based mapping of tertiary lymphoid structure scores from H&E images of renal cell carcinoma trained by spatial transcriptomics data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5420.

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Rustamkhanov, R. A., K. Sh Gantsev, and D. S. Tursumetov. "Tertiary Lymphoid Structures and Cancer Prognosis (Brief Review)." Creative surgery and oncology 9, no. 4 (January 24, 2020): 293–96. http://dx.doi.org/10.24060/2076-3093-2019-9-4-293-296.

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This brief review is devoted to the role of tertiary lymphoid structures in oncological processes. A number of research studies carried out over the past ten years have shed light on the functions of such structures in various diseases, as well as their role in the progression of the pathological process or resolution of a disease. The data presented in some research works confirms the relationship between the presence of tumour-specific (tumour-associated) tertiary lymphoid structures and a favourable prognosis in patients with various oncological diseases, which suggests the participation of tertiary lymphoid structures in effective local antitumour immune responses. However, no reliable evidence has so far been obtained that could confirm the contribution of tertiary lymphoid structures to immune processes in vivo, with the available information being largely of a correlative character. It should be emphasized that the clinical significance of tertiary lymphoid structures ranges from a destructive to protective impact, which indicates the need for an improved understanding of the structure and case-specific function of these organs before conducting clinical targeting.

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Robles, Marcel R., Michael Malkowski, and Sandeep Krishnan. "S1842 Tertiary Lymphoid Structure Mimicking Pancreatic Mass." American Journal of Gastroenterology 117, no. 10S (October 2022): e1285-e1286. http://dx.doi.org/10.14309/01.ajg.0000864008.96774.a4.

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

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

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Gorecki, Grace, Lan Gardner Coffman, Sarah E. Taylor, and Tullia C. Bruno. "Tertiary lymphoid structure prevalence and prognostic value in cervical cancer." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e17521-e17521. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e17521.

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

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Sunyer, J. Oriol, Yasuhiro Shibasali, Fumio Takizawa, Ding Yang, Pierre Boudinot, and Aleksei Krasnov. "IDENTIFICATION OF PRIMORDIAL ORGANIZED LYMPHOID STRUCTURE IN THE SPLEEN OF TELEOST FISH." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 92.40. http://dx.doi.org/10.4049/jimmunol.204.supp.92.40.

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Abstract Induction of adaptive immune responses in higher vertebrate species occur within organized lymphoid structures (e.g. lymph nodes, Peyer’s patches). It has been proposed that such structures emerged throughout evolutionary time with the goal to maximize encounters between antigens, antigens-presenting cells and B-T lymphocytes. Fish lack such structures and thus, it remains unknown how and where antigen-specific immunoglobulin responses are induced in these species. To understand how systemic immune responses are induced in teleost lymphoid organs, Rainbow Trout were immunized with several soluble protein antigens. Overall, our results identified the spleen as the major site for CD4+ T and IgM+ B cell proliferation in systemic lymphoid organs upon immunization. The proliferating splenic IgM+ B cells were frequently observed as clusters in the vicinity of melano-macrophage centers. Moreover, in these areas we observed aggregates of B and T lymphocytes with a loose organized structure reminiscent of the cellular architecture frequently associated with tertiary lymphoid organs. Laser dissection microdissection of these areas enabled us to evaluating the immunoglobulin IgM repertoires within these structures upon immunization. Critically, repertoire analysis identified processes of antigen-specific B cell clonal expansion. In conclusion, these data points to the previously unrecognized existence of primordial semi-organized lymphoid tissue in the spleen of teleost fish in which adaptive IgM immune responses are induced. Our findings provide strong evidence that the induction of antigen-specific immune responses in all bony vertebrates requires the formation of organized or semi-organized lymphoid structures.

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HAYASE, SHIMON, NORIKATSU MIYOSHI, SHIKI FUJINO, MASAYOSHI YASUI, MASAYUKI OHUE, SOICHIRO MINAMI, SHINYA KATO, et al. "Fibroblast Activation Protein and Tertiary Lymphoid Structure in Colorectal Cancer Recurrence." Anticancer Research 42, no. 12 (December 2022): 5897–907. http://dx.doi.org/10.21873/anticanres.16099.

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

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

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

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Erlich, Emma, Rafael Czepielewski, Shashi Kumar, Rachael Field, Xinya Zhang, Leila Saleh, Farshid Guilak, Jonathan Brestoff, Ali Ellebedy, and Gwendalyn J. Randolph. "B cells drive tertiary lymphoid organ formation in ileal inflammation." Journal of Immunology 208, no. 1_Supplement (May 1, 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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Briem, Oscar, Eva Källberg, Siker Kimbung, Srinivas Veerla, Jenny Stenström, Thomas Hatschek, Catharina Hagerling, Ingrid Hedenfalk, and Karin Leandersson. "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 (February 16, 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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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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Jiang, Quan, Chenyu Tian, Hao Wu, Lingqiang Min, Hao Chen, Lingli Chen, Fenglin Liu, and Yihong Sun. "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, 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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Hill, David G., Liang Yu, Hugh Gao, Jesse J. Balic, Alison West, Hiroko Oshima, Louise McLeod, et al. "Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development." International Journal of Cancer 143, no. 1 (February 19, 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, 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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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 (May 1, 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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Ichii, Osamu, Marina Hosotani, Md Abdul Masum, Taro Horino, Yuki Otani, Takashi Namba, Teppei Nakamura, Elewa Yaser Hosny Ali, and Yasuhiro Kon. "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 (October 22, 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 (November 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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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 (December 13, 2021): 4–6. http://dx.doi.org/10.1681/asn.2021111465.

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Wang, Jin, Dongbo Jiang, Xiaoqi Zheng, Wang Li, Tian Zhao, Di Wang, Huansha Yu, et al. "Tertiary lymphoid structure and decreased CD8+ T cell infiltration in minimally invasive adenocarcinoma." iScience 25, no. 3 (March 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 (August 2024): S151. http://dx.doi.org/10.1016/j.jid.2024.06.1247.

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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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Cho, Kyung Serk, Jiahui Jiang, Daiwei Zhang, Yunhe Liu, Jianfeng Chen, Rossana L. Segura, Xinmiao Yan, et al. "Abstract 7424: iStarTLS: Advanced detection and phenotyping of tertiary lymphoid structures." Cancer Research 84, no. 6_Supplement (March 22, 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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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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Zhao, Zhan, Hui Ding, Zheng-bin Lin, Sheng-hui Qiu, Yi-ran Zhang, Yan-guan Guo, Xiao-dong Chu, Loi I. Sam, Jing-hua Pan, and Yun-long Pan. "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, 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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Buisseret, Laurence, Christine Desmedt, Soizic Garaud, Marco Fornili, Xiaoxiao Wang, Gert Van den Eyden, Alexandre de Wind, et al. "Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer." Modern Pathology 30, no. 9 (June 16, 2017): 1204–12. http://dx.doi.org/10.1038/modpathol.2017.43.

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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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He, Miao, Qihua He, Xiuyu Cai, Jun Liu, Hongshen Deng, Feng Li, Ran Zhong, 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 (April 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 (March 22, 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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Lin, Qiaowei, Ping Tao, Jiongyuan Wang, Lijie Ma, Quan Jiang, Jinglei Li, Ge Zhang, et al. "Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors." OncoImmunology 9, no. 1 (January 1, 2020): 1747339. http://dx.doi.org/10.1080/2162402x.2020.1747339.

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石, 文. "Establishment and Validation of LncRNA Prognostic Indicators Related to Tertiary Lymphoid Structure in Hepatocellular Carcinoma." Advances in Clinical Medicine 13, no. 10 (2023): 15504–16. http://dx.doi.org/10.12677/acm.2023.13102169.

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Tanaka, Takeshi, Atsuhiro Masuda, and Yuzo Kodama. "Tu1428 ELUCIDATION OF TUMOR IMMUNE SYSTEM MEDIATED BY TLS (TERTIARY LYMPHOID STRUCTURE) IN PANCREATIC CANCER." Gastroenterology 166, no. 5 (May 2024): S—1336. http://dx.doi.org/10.1016/s0016-5085(24)03518-2.

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Gomez Medellin, Jorge E., Maile Kananiokala Hollinger, Jillian Rosenberg, Kelly Blaine, Trevin Kurtanich, Nick Ankenbruck, Cara Lynn Hrusch, Anne I. Sperling, and Melody A. Swartz. "VEGFR3-driven pulmonary lymphangiogenesis exacerbates induction of bronchus-associated lymphoid tissue in allergic airway disease." Journal of Immunology 208, no. 1_Supplement (May 1, 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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Koscsó, Balázs, Sravya Kurapati, Richard R. Rodrigues, Jelena Nedjic, Kavitha Gowda, Changsik Shin, Chetna Soni, et al. "Gut-resident CX3CR1hi macrophages induce tertiary lymphoid structures and IgA response in situ." Science Immunology 5, no. 46 (April 10, 2020): eaax0062. http://dx.doi.org/10.1126/sciimmunol.aax0062.

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Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2+CX3CR1lo, Ccr7+CX3CR1int (lymph migratory), and Cxcl13+CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13+CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7+CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.

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Liu, Xia, Julia Y. S. Tsang, Thazin Hlaing, Jintao Hu, Yun‐Bi Ni, Siu Ki Chan, Sai Yin Cheung, and Gary M. Tse. "Distinct Tertiary Lymphoid Structure Associations and Their Prognostic Relevance in HER2 Positive and Negative Breast Cancers." Oncologist 22, no. 11 (July 12, 2017): 1316–24. http://dx.doi.org/10.1634/theoncologist.2017-0029.

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Zhou, Lin, Bin Xu, Yushan Liu, and Zhong Wang. "Tertiary lymphoid structure signatures are associated with survival and immunotherapy response in muscle-invasive bladder cancer." OncoImmunology 10, no. 1 (January 1, 2021): 1915574. http://dx.doi.org/10.1080/2162402x.2021.1915574.

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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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An, Disi, Guoying Chen, Wei Wang, Katja Mohrs, David DiLillo, Christopher Daly, Gavin Thurston, et al. "Abstract 4134: Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4134. http://dx.doi.org/10.1158/1538-7445.am2023-4134.

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Abstract High endothelial venules (HEV) are specialized blood vessels that mediate lymphocyte trafficking to lymph nodes. Tertiary lymphoid structures (TLS) are ectopic lymphoid formations that develop in inflamed, infected or tumoral tissues. TLS contain HEV and B cell follicles surrounded by a T-cell zone and are characterized by abundant chemokine expression. The presence of TLS and HEV in solid tumors is positively correlated with patient survival in many cancer types, and may even be predictive of better response to immune-checkpoint blockade. However, the molecular mechanisms underlying the intratumoral HEV and TLS formation remain unclear. Using murine syngeneic tumor models, we found that systemic activation of lymphotoxin beta receptor (LTBR) with an agonistic antibody induced tumor-specific HEV formation, increased dendritic cell (DC) and T cell infiltration, and enhanced T cell activation in the tumor. In vitro assays revealed that LTBR agonism directly upregulated activation and maturation markers in bone marrow-derived DCs and promoted DC-mediated CD4 and CD8 T cell activation. Single agent LTBR agonist treatment attenuated Colon26 tumor growth in a CD8 T cell-dependent manner. In combination treatment studies, LTBR agonism further augmented anti-tumor efficacy of anti-PD1 and of CAR-T therapy. Notably, LTBR agonist mAb treatment upregulated the expression of TLS-related chemokines and induced TLS-like structures in approximately 20% of treated tumors. To enhance TLS induction, we generated syngeneic tumor models engineered to express several cytokines/chemokines and performed an in vivo screen for tumor-associated TLS formation. We identified some factors that in combination with LTBR agonism induced B cell enrichment and immature TLS formation, while others promoted robust TLS induction and anti-tumor effect. TLS formation induced by combined LTBR agonism and cytokine expression is associated with augmented anti-tumor responses to anti-CTLA-4 treatment. By studying anti-tumor mechanisms of LTBR agonism-mediated HEV and TLS formation, this work informs the future therapeutic strategies to boost T cell infiltration and activation in solid tumors. Citation Format: Disi An, Guoying Chen, Wei Wang, Katja Mohrs, David DiLillo, Christopher Daly, Gavin Thurston, John Lin, Namita Gupta, Mickey Atwal, Frank Kuhnert. Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism. [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 4134.

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Cameron, Andrew J., Assya Legrini, Colin S. Wood, Craig Nourse, Yoana Doncheva, Claire Kennedy Dietrich, Colin Nixon, et al. "Abstract A028: Multiomic modelling of pancreatic IPMN stroma reveals distinct tertiary lymphoid structure distribution: Mapping the transcriptomic landscape via regional bulk, single-cell and subcellular approaches." Cancer Research 84, no. 2_Supplement (January 16, 2024): A028. http://dx.doi.org/10.1158/1538-7445.panca2023-a028.

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Abstract Background Intraductal Papillary Mucinous Neoplasms (IPMN) remain the largest subtype of cystic pancreatic cancer precursors. Cancer risk has been observed to vary between histological grades and histological subtypes. Spatial characterisation has revealed variation in immune cell distribution disease subtypes. Methods A cohort of 14 surgically resected IPMN tumors across a range of histological grades (Low-grade LG, high-grade HG and invasive IPMN cancers IPMN-PDAC) and subtypes (gastric, intestinal, pancreaticobiliary) underwent multimodal spatial interrogation. After expert histopathological annotation; tissue sections underwent regional whole transcriptome analysis with TempO-seq and 10x Visium. Extensive region analysis with NanoString GeoMx employing segmentation using staining for epithelium (PanCK) fibroblast stroma (aSMA) was performed. A tissue microarray was then constructed, and representative cores underwent single-cell and subcellular spatial transcriptomic analysis with NanoString CosMx. Raw count data and digital images were exported and analysed using Seurat, Giotto, SPATA2 and custom R pipelines. Region deconvolution, Harmony integration, Leiden Clustering, Gene Set Enrichment Analysis, Trajectory Mapping, and Moran’s I Analysis were performed. Results TempO-seq revealed up-regulation of canonical oncogene expression in all IPMN-PDAC cases as compared to LG and HG IPMN. There were no statistically significant differences in expression comparing LG and HG IPMN lesions. Visium differential gene expression and clustering models identified cancer epithelium, stroma and lymphatic components that correlated with histopathological annotations. Immune cell rich spots were identified via gene ontology of top 50 marker genes. The spatial trajectory of B-cell expression signatures in IPMN-PDAC showed greater concentration and less variability than HG tumors, Moran’s I -0.34 vs 0.12 (P = 0.021). B-cells in HG IPMN were showed greater concentration and less variability than LG IPMN, Moran’s I -0.15 vs 0.02 (P=0.05). Much of this concentration was in identified lymphoid aggregates or tertiary lymphoid structures. The spatial trajectory of T-cell expression. The spatial trajectory of macrophage expression showed greater concentration and less variability than in LG and HG tumors. GeoMx analysis of stromal regions identified up regulation of B cell signatures in IPMN PDAC and HG IPMN when compared to LG IPMN. Markers associated with TLS formation were found to be significantly upregulated including CXCL13, CXCR5 and LAMP3. Pancreaticobiliary subtypes were found to have the least concentrated B-cell distribution across subtypes. Conclusions Immune cell composition was found to vary across histological grades and subtypes of IPMN. A paradoxical relationship was observed between T-cell infiltrates and B-cell and macrophage populations. The greater proportion of tertiary lymphoid structures, and high levels of TLS specific gene expression, may indicate a propensity for b-cell activation in IPMN tumors which progress to malignancy. Citation Format: Andrew J. Cameron, Assya Legrini, Colin S. Wood, Craig Nourse, Yoana Doncheva, Claire Kennedy Dietrich, Colin Nixon, Jennifer Hay, Fraser Duthie, Pawel Herzyk, Jennifer Morton, Nigel B. Jamieson. Multiomic modelling of pancreatic IPMN stroma reveals distinct tertiary lymphoid structure distribution: Mapping the transcriptomic landscape via regional bulk, single-cell and subcellular approaches [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A028.

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Lyapunova, Liliya, Lyubov Tashireva, and Vladimir Perelmuter. "FOLLICULAR T-HELPER LYMPHOCYTES AND THEIR SIGNIFICANCE IN CANCER." Problems in oncology 63, no. 6 (June 1, 2017): 824–30. http://dx.doi.org/10.37469/0507-3758-2017-63-6-824-830.

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The variety of cells, which are presented in the tumor microenvironment complicate comprehension of their effects. The population of T-helper lymphocytes has also expressed heterogeneity. However it becomes clearer that effects of separate cells are defined by their role in formation together with other participants the corresponding type of immuno-inflammatory reaction in a microenvironment. The follicular T-helper lymphocytes that are in tumor both in the structure of the tertiary lymphoid structures that have the architectonics of the lymph node and outside of them are not an exception. This review presents the history of discovery follicular T-helper cells population and stages of their maturation, describes feature of phenotype and considers heterogeneity inside subset of these cells. Furthermore the data about correlation between follicular T-helper cells and tumor disease are presented.

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Chelvanambi, Manoj, Ronald J. Fecek, Jennifer L. Taylor, and Walter J. Storkus. "STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment." Journal for ImmunoTherapy of Cancer 9, no. 2 (February 2021): e001906. http://dx.doi.org/10.1136/jitc-2020-001906.

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BackgroundThe degree of immune infiltration in tumors, especially CD8+ T cells, greatly impacts patient disease course and response to interventional immunotherapy. Enhancement of tumor infiltrating lymphocyte (TIL) is a critical element of efficacious therapy and one that may be achieved via administration of agents that promote tumor vascular normalization (VN) and/or induce the development of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME).MethodsLow-dose stimulator of interferon genes (STING) agonist ADU S-100 (5 µg/mouse) was delivered intratumorally to established subcutaneous B16.F10 melanomas on days 10, 14 and 17 post-tumor inoculation. Treated and control tumors were isolated at various time points to assess transcriptional changes associated with VN and TLS formation via quantitative PCR (qPCR), with corollary immune cell composition changes in isolated tissues determined using flow cytometry and immunofluorescence microscopy. In vitro assays were performed on CD11c+ BMDCs treated with 2.5 µg/mL ADU S-100 or CD11c+ DCs isolated from tumor digests and associated transcriptional changes analyzed via qPCR or profiled using DNA microarrays. For T cell repertoireβ-CDR3 analyses, T cell CDR3 was sequenced from gDNA isolated from splenocytes and enzymatically digested tumors.ResultsWe report that activation of STING within the TME leads to slowed melanoma growth in association with increased production of antiangiogenic factors including Tnfsf15 (Vegi) and Cxcl10, and TLS-inducing factors including Ccl19, Ccl21, Lta, Ltb and Light. Therapeutic responses resulting from intratumoral STING activation were characterized by improved VN, enhanced tumor infiltration by CD8+ T cells and CD11c+ DCs and local TLS neogenesis, all of which were dependent on host expression of STING. Consistent with a central role for DC in TLS formation, ADU S-100-activated mCD11c+ DCs also exhibited upregulated expression of TLS promoting factors including lymphotoxin-α (LTA), interleukin (IL)-36, inflammatory chemokines and type I interferons in vitro and in vivo. TLS formation in ADU S-100-treated mice was associated with the development of a highly oligoclonal TIL repertoire enriched in expanded T cell clonotypes unique to the TME and not detected in the periphery.ConclusionsOur data support the premise that i.t. delivery of low-dose STING agonist promotes VN and a proinflammatory TME supportive of TLS formation, enrichment in the TIL repertoire and tumor growth control.

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Lin, Jamie, Amanda Tchakarov, Noha Abdel-Wahab, Houssein Safa, Salah-Eddine Bentebibel, Maen Abdelrahim, Cassian Yee, Adi Diab, and Ala Abudayyeh. "808 Tertiary lymphoid structure gene signature detected in immune checkpoint inhibitor-associated renal immune related adverse event." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A845. http://dx.doi.org/10.1136/jitc-2021-sitc2021.808.

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BackgroundTertiary lymphoid structures (TLSs) have been previously associated with ICI induced response in patients with cancer, but a commensurate observation has not been made in ICI associated immune related adverse events (irAEs). Acute interstitial nephritis (AIN) is the predominant lesion reported in patients with renal irAEs, but various etiologies can also trigger the development of AIN including non-ICI drugs (e.g. non-steroidal anti-inflammatory drugs, antibiotics, proton pump inhibitors, etc.), and it is unknown whether these mechanisms are similar. With increasing indications for ICIs in cancer therapy, there is a critical need to define immune pathways driving the emergence of irAEs. To address this critical knowledge gap, we performed gene expression profiling on ICI-AIN, drug-AIN, and control (non-AIN) kidney biopsy specimens.MethodsTotal RNA extracted from ICI-AIN (n = 6), drug-AIN (n = 4), and control (n = 4) fixed formalin paraffin embedded archival kidney biopsy samples was analyzed by Nanostring nCounter PanCancer Immune Profiling Panel using NanoString nCounter FLEX Analysis System.ResultsThree comparisons were conducted: ICI-AIN vs control, drug-AIN vs control, and ICI-AIN vs drug-AIN. A total of 147 genes were differentially expressed in ICI-AIN vs control and the most differentially expressed genes were CXCL 9, 10, and 11. Similarly, cell marker gene expression signatures (GES) revealed significant upregulation of T and B cell markers in ICI-AIN vs control (P < 0.01) and ICI-AIN vs drug-AIN (T cell P < 0.05; B cell P < 0.01). Differences in T and B cell score were not detected in drug-AIN vs control. Since irAEs have been associated with anti-tumor efficacy, we investigated whether a TLS signature could be detected in ICI-AIN using a four GES (CD79A, MS4A1, LAMP3 and POU2AF1). The ICI-AIN group had significantly higher TLS score compared to both control and drug-AIN groups. Since several TLS signatures have been reported, we also calculated a 12-chemokine TLS GES which was also found to be statistically significant (P < 0.05). Th1 and Th17 cells have been associated with the formation of TLS, differential upregulation of Th1 associated genes but not Th17 associated genes were detected. Furthermore, differential expression IFN-y and TNF signature was also observed in ICI-AIN group.ConclusionsThis study is the first to demonstrate the presence of TLS immune signature in irAEs. Further investigations into the prognostic significance and strategies to uncouple ICI-associated anti-tumor benefits from ICI-induced irAEs should be explored.Ethics ApprovalThe study was approved by The University of Texas MD Anderson Cancer Center intuition's Ethics Board, approval number PA16-1016

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Yin, Xuewen, Hui Wang, Rutao Li, Xuming Song, Te Zhang, Yingkuan Liang, Yu-Zhong Chen, et al. "Tobacco exposure primes the secretion of CCL21 positively associated with tertiary lymphoid structure and response to immunotherapy." Journal for ImmunoTherapy of Cancer 11, no. 6 (June 2023): e006939. http://dx.doi.org/10.1136/jitc-2023-006939.

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BackgroundIt has been reported that smoking history as a predictor of immunotherapy efficacy in patients with advanced lung cancer, however, the underlying mechanisms of this phenomenon remain largely unknown.MethodsThe patients with lung adenocarcinoma’s (LUAD) cohort and the orthotopical transplanted mouse model were used to explore the correlation between smoking status and tertiary lymphoid structure (TLS) and chemokine CCL21, respectively. Cell adhesion and co-immunoprecipitation assays were performed to explore the interaction between CD4+T cells and CD20+B cells under tobacco exposure. Chromatin immunoprecipitation-PCR was used to dissect the mechanism of upregulated CCL21 secretion in tobacco treatment. Serum CCL21 level was recorded in patients with LUAD treated with immunotherapy.ResultsHere we observed that individuals with a smoking history exhibit an increased quantity and maturation level of TLS compared with non-smokers, along with higher levels of CCL21 secretion. Tobacco exposure promoted CCL21 expression in an epithelial cell-intrinsic manner, of which BaP, the main component of tobacco, facilitated the nuclear retention of the aryl hydrocarbon receptor that occupied the promoter of CCL21. Additionally, the activated CCL21/CCR7 axis increased the CD11a expression of CD4+T cells, boosting the interaction with CD20+B cells dependent on ICAM1, which potentially induced the TLSs formation. Patients with elevated serum levels of CCL21 benefited more from immunotherapy.ConclusionsPatients with a smoking history exhibited higher levels of TLS via the CCL21-dependent mechanism, serum CCL21 was identified as a reliable biomarker for predicting the efficacy of immunotherapy.

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Sun, Kang, Zhiqiang Zhang, Dongqin Wang, Yinlong Huang, Jing Zhang, and Chaoqun Lian. "B cell-related tertiary lymphoid structure may exert inhibitory effects on lung adenocarcinoma and SARS-COV-2." Heliyon 9, no. 3 (March 2023): e14334. http://dx.doi.org/10.1016/j.heliyon.2023.e14334.

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Zhou, S., C. Zhu, X. Xia, F. Yao, Y. Lin, and N. Shao. "256P Protein signature of tertiary lymphoid structure predicts efficacy of neoadjuvant chemotherapy in triple-negative breast cancer." Annals of Oncology 35 (September 2024): S322. http://dx.doi.org/10.1016/j.annonc.2024.08.199.

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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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