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Draft:Tertiary Lymphoid Structure

From Wikipedia, the free encyclopedia

Tertiary lymphoid structures (TLS), also known as tertiary lymphoid organs (TLOs), are aggregates of immune cells that form in non-lymphoid tissues. [1][2] While primary and secondary lymphoid organs are found in healthy tissue at specific anatomical locations, TLS are not normally present under healthy physiological conditions. [3][4] TLS develop ectopically in response to continuous inflammation in peripheral tissues, at sites of chronic inflammation, chronic infection, autoimmune disease, transplanted organs undergoing graft rejection, and cancer. [1][3]

The definition of TLS has not yet reached consensus within the field and can vary across studies. TLS are usually defined as a tight cluster of T cells and B cells in distinct but adjacent zones, similar to secondary lymphoid organs.[5] Although their formation follows a different process from the normal ontogenetic development of lymphoid tissue, TLS have functional roles similar to those of secondary lymphoid organs.[2][6] TLS development relies on cytokine signalling and haematopoietic cell involvement, and they are involved in lymphocyte trafficking through similar chemical messengers and signalling gradients as secondary lymphoid organs.[2][6]

Terminology

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"Tertiary lymphoid structure" and "tertiary lymphoid organ" are used interchangeably in the literature. They are also be referred to as ectopic lymphoid structures, ectopic lymphoid tissue, or ectopic lymphoid follicles.[7][8] Since TLS lack the defining features of an organ, the term "structure" has more recently become preferred in the field.[9] Unlike secondary lymphoid organs, TLS lack a stable structural organization, such as a fibrous capsule, and afferent lymphatic vessels. [10] TLS are not permanent structures and have a variable organisation.[9] TLS are not present in embryonic life, only forming in adult tissue to support the ectopic local aggregation of lymphocytes.[9]

The term "tertiary" differentiates TLS from primary and secondary lymphoid organs, which are known, respectively, to originate lymphocytes and to enable antigen-specific activation of lymphocytes under normal physiological conditions. [6]

Structure and composition

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TLS composition can range from a simple, loose lymphoid aggregate to a highly organized structure similar to secondary lymphoid organs. [5] Based on the activation and composition of the cells within TLS, they have been described in three organisational stages: early TLS; primary follicle-like TLS and secondary follicle-like TLS.[11][12] Recent advances indicate that TLS maturation can also be dependent on the inflammatory condition and the specific tissue involved.[11]

Early TLS are characterized by clusters of lymphoid cells without follicular dendritic cells (FDCs) and occasionally dendritic cells. [11][12] Primary follicle-like TLS, also known as immature TLS, have distinct T cell and B cell cluster zones with FDCs but without a germinal center. [11][12] Secondary follicle-like TLS, or mature TLS, are ssimilar to lymph nodes structurally and functionally, as TLS contain adjacent T cell and follicular B cell zones with dendritic cells that can develop into a functional germinal center, [4][13] and often have high endothelial venules (HEVs) that activate and recruit lymphocytes from the blood. [3][13]

Within the T cell compartment, CD4+ T follicular helper (Tfh) cells are typically the dominant subset, along with variable numbers of CD8+ cytotoxic T cells, CD4+ T helper 1 (Th1) cells, and regulatory T cells(Tregs).[2][12] Within the B-cell compartment, there are typically naive immunoglobulin D+ (IgD+) B cells surrounding the germinal centre, which is defined by proliferating Ki67+CD23+ B cells and CD21+ FDCs, resembling secondary lymphoid organs.[2][12]

TLS in disease settings

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Cancer

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TLS have been reported in a wide range of solid tumours, including head and neck cancer,[14] breast cancer,[15] non-small cell lung cancer,[16] ovarian cancer,[17] colorectal cancer,[18] hepatocellular carcinoma,[19] cholangiocarcinoma,[20] renal cancer,[21] bladder cancer,[22] gastric cancer,[23] oesophageal cancer,[24] uterine cancer,[25] pancreatic cancer,[26] skin cancer,[27] and other tumours. TLS are intricately associated with cancer prognosis, tumor progression, and immune responses.

TLS in different tumors may display functional heterogeneity, ranging from immune-stimulatory to immune-suppressive states depending on their maturation stage, composition, and location. [28] Across most cancer types studied, the presence of TLSs is accompanied by the formation of high endothelial venules (HEVs), increased immune infiltration, and elevated multiple lymphoid chemokines, which correlates with favourable prognosis.[2] TLS has also been linked to tumor progression in some cancer types through several potential immunosuppressive mechanisms.[29][30] In lung adenocarcinoma, the presence of regulatory T (Treg) cells in TLS has been reported to inhibit endogenous immune response, linking to poor prognosis. [31]

Autoimmune and chronic inflammatory disease

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Tissue with chronic autoimmune and inflammatory conditions may also drive the formation of TLS, which has been reported in rheumatoid arthritis (RA),[32] systemic lupus erythematosus (SLE),[33] Sjögren syndrome (SS),[34] pemphigus,[35] autoimmune encephalomyelitis,[36] diabetes mellitus,[37] uveitis,[38] giant cell arteritis,[39] and dermatomyositis.[40] In autoimmune and chronic inflammatory diseases, the presence of TLS is associated with autoantibody production and local immune activation, which can lead to tissue destruction and fibrosis.[41][42] TLS are usually associated with disease persistence and worse clinical outcomes, although their pathogenic role is still debated and likely depends on the organ and disease type.[9]

References

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  1. 1 2 Yin, C.; Mohanta, S.; Maffia, P.; Habenicht, A. J. R. (2017). "Editorial: Tertiary Lymphoid Organs (TLOs): Powerhouses of Disease Immunity". Frontiers in Immunology. 8: 228. doi:10.3389/fimmu.2017.00228. PMC 5337484. PMID 28321222.
  2. 1 2 3 4 5 6 Schumacher, T. N.; Thommen, D. S. (2022). "Tertiary lymphoid structures in cancer". Science. 375 (6576) eabf9419. Bibcode:2022Sci...375f9419S. doi:10.1126/science.abf9419. PMID 34990248.
  3. 1 2 3 Li, Hao; Ding, Jia-Yi; Zhang, Meng-Jie; Yu, Hai-Jun; Sun, Zhi-Jun (2023). "Tertiary lymphoid structures and cytokines interconnections: The implication in cancer immunotherapy". Cancer Letters. 568 216293. doi:10.1016/j.canlet.2023.216293. PMID 37392991.
  4. 1 2 Zhang, Qianqian; Wu, Suhui (2023). "Tertiary lymphoid structures are critical for cancer prognosis and therapeutic response". Frontiers in Immunology. 13 1063711. doi:10.3389/fimmu.2022.1063711. PMC 9875059. PMID 36713409.
  5. 1 2 van de Walle, Tiarne; Vaccaro, Alessandra; Ramachandran, Mohanraj; Pietilä, Ilkka; Essand, Magnus; Dimberg, Anna (2021). "Tertiary Lymphoid Structures in the Central Nervous System: Implications for Glioblastoma". Frontiers in Immunology. 12 724739. doi:10.3389/fimmu.2021.724739. PMC 8442660. PMID 34539661.
  6. 1 2 3 Ruddle, Nancy H. (2014). "Lymphatic vessels and tertiary lymphoid organs". Journal of Clinical Investigation. 124 (3): 953–959. doi:10.1172/JCI71611. PMC 3934190. PMID 24590281.
  7. ↑ "Tertiary Lymphoid Structures". Medical Subject Headings (MeSH). National Library of Medicine (US). 2024. Retrieved 2026-09-16.
  8. ↑ <ref>Rochefort, Juliette; Marodon, Gilles; Teillaud, Jean-Luc; Dieu-Nosjean, Marie-Caroline (2025). "The Sunrise of Tertiary Lymphoid Structures in Cancer". Immunological Reviews. 332 (1) e70046. doi:10.1111/imr.70046. PMC 12212410. PMID 40591148.
  9. 1 2 3 4 Pipi, Elena; Nayar, Saba; Gardner, David H.; Colafrancesco, Serena; Smith, Charlotte; Barone, Francesca (2018). "Tertiary Lymphoid Structures: Autoimmunity Goes Local". Frontiers in Immunology. 9 1952. doi:10.3389/fimmu.2018.01952. PMC 6143705. PMID 30258435.
  10. ↑ Corsiero, Elisa; Delvecchio, Francesca Romana; Bombardieri, Michele; Pitzalis, Costantino (2019). "B cells in the formation of tertiary lymphoid organs in autoimmunity, transplantation and tumorigenesis". Current Opinion in Immunology. 57: 46–52. doi:10.1016/j.coi.2019.01.004. PMID 30798069.
  11. 1 2 3 4 Vaccaro, Alessandra; van de Walle, Tiarne; Ramachandran, Mohanraj; Essand, Magnus; Dimberg, Anna (2023). "Of mice and lymphoid aggregates: modeling tertiary lymphoid structures in cancer". Frontiers in Immunology. 14 1275378. doi:10.3389/fimmu.2023.1275378. PMC 10639130. PMID 37954592.
  12. 1 2 3 4 5 Teillaud, Jean-Luc; Houel, Ana; Panouillot, Marylou; Riffard, Clémence; Dieu-Nosjean, Marie-Caroline (2024). "Tertiary lymphoid structures in anticancer immunity". Nature Reviews Cancer. 24 (9): 629–646. doi:10.1038/s41568-024-00728-0. PMID 39117919.
  13. 1 2 Sautès-Fridman, Catherine; Petitprez, Florent; Calderaro, Julien; Fridman, Wolf Herman (2019). "Tertiary lymphoid structures in the era of cancer immunotherapy". Nature Reviews Cancer. 19 (6): 307–325. doi:10.1038/s41568-019-0144-6. PMID 31092904.
  14. ↑ Ruffin, Ayana T.; Cillo, Anthony R.; Tabib, Tracy; Liu, Angen; Onkar, Sayali; Kunning, Sheryl R.; Lampenfeld, Caleb; Atiya, Huda I.; Abecassis, Irina; Kürten, Cornelius H. L.; Qi, Zengbiao; Soose, Ryan; Duvvuri, Umamaheswar; Kim, Seungwon; Oesterrich, Steffi; Lafyatis, Robert; Coffman, Lan G.; Ferris, Robert L.; Vignali, Dario A. A.; Bruno, Tullia C. (2021). "B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma". Nature Communications. 12 (1): 3349. Bibcode:2021NatCo..12.3349R. doi:10.1038/s41467-021-23355-x. PMC 8184766. PMID 34099645.
  15. ↑ Wang, Qing; Sun, Ke; Liu, Rui (2023). "Single-cell transcriptome sequencing of B-cell heterogeneity and tertiary lymphoid structure predicts breast cancer prognosis and neoadjuvant therapy efficacy". Clinical and Translational Medicine. 13 (8) e1346. doi:10.1002/ctm2.1346. PMC 10390819. PMID 37525587.
  16. ↑ Sun, Xiaoyan; Liu, Weiran (2022). "Maturation and abundance of tertiary lymphoid structures are associated with the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer". Journal for ImmunoTherapy of Cancer. 10 (11) e005531. doi:10.1136/jitc-2022-005531. PMC 9644367. PMID 37011953.
  17. ↑ Feng, Wangyou; Jiang, Dongbo; Xu, Ying (2023). "CDK4/6i enhances the antitumor effect of PD1 antibody by promoting TLS formation in ovarian cancer". Heliyon. 9 (9) e19760. Bibcode:2023Heliy...919760F. doi:10.1016/j.heliyon.2023.e19760. PMC 10559077. PMID 37809574.
  18. ↑ Zhang, Chong; Wang, Xiang-Yu; Zuo, Jie-Liang (2023). "Localization and density of tertiary lymphoid structures associate with molecular subtype and clinical outcome in colorectal cancer liver metastases". Journal for ImmunoTherapy of Cancer. 11 (2) e006425. doi:10.1136/jitc-2022-006425. PMC 9923349. PMID 36759015.
  19. ↑ Calderaro, Julien; Petitprez, Florent; Becht, Etienne; Laurent, Alexis; Hirsch, Théo Z.; Rousseau, Benoît; Luciani, Alain; Amaddeo, Giuliana; Derman, Jonathan; Charpy, Cecile; Zucman-Rossi, Jessica; Fridman, Wolf Herman; Sautès-Fridman, Catherine (2019). "Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma". Journal of Hepatology. 70 (1): 58–65. doi:10.1016/j.jhep.2018.09.003. PMID 30213589.
  20. ↑ Zhang, Fa-Peng; Zhu, Ke; Zhu, Tai-Feng; Liu, Chao-Qun; Zhang, Hong-Hua; Xu, Lei-Bo; Xiao, Gang; Liu, Chao (2022). "Intra-Tumoral Secondary Follicle-like Tertiary Lymphoid Structures Are Associated with a Superior Prognosis of Overall Survival of Perihilar Cholangiocarcinoma". Cancers. 14 (24): 6107. doi:10.3390/cancers14246107. PMC 9776022. PMID 36551593.
  21. ↑ Masuda, Tsukasa; Tanaka, Nobuyuki; Takamatsu, Kimiharu (2022). "Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer". Journal for ImmunoTherapy of Cancer. 10 (3) e003883. doi:10.1136/jitc-2021-003883. PMC 8938705. PMID 35314433.
  22. ↑ Groeneveld, Clarice S.; Fontugne, Jacqueline; Cabel, Luc; Bernard-Pierrot, Isabelle; Radvanyi, François; Allory, Yves; de Reyniès, Aurélien (2021). "Tertiary lymphoid structures marker CXCL13 is associated with better survival for patients with advanced-stage bladder cancer treated with immunotherapy". European Journal of Cancer. 148: 181–189. doi:10.1016/j.ejca.2021.01.036. PMID 33743486.
  23. ↑ Yin, Yi-Xin; Ling, Yi-Hong; Wei, Xiao-Li (2022). "Impact of mature tertiary lymphoid structures on prognosis and therapeutic response of Epstein-Barr virus-associated gastric cancer patients". Frontiers in Immunology. 13 973085. doi:10.3389/fimmu.2022.973085. PMC 9794571. PMID 36591236.
  24. ↑ Wang, Yihong; Zhong, Jian; Weng, Zelin (2022). "The prognostic value and molecular properties of tertiary lymphoid structures in oesophageal squamous cell carcinoma". Clinical and Translational Medicine. 12 (10) e1074. doi:10.1002/ctm2.1074. PMC 9574489. PMID 36245289.
  25. ↑ Horeweg, Nanda; Workel, Hagma H.; Loiero, Dominik (2022). "Tertiary lymphoid structures critical for prognosis in endometrial cancer patients". Nature Communications. 13 (1): 1373. Bibcode:2022NatCo..13.1373H. doi:10.1038/s41467-022-29040-x. PMC 8927106. PMID 35296668.
  26. ↑ Gunderson, Andrew J.; Rajamanickam, Venkatesh; Buia, Cynthia; Bifulco, Carlo; Crittenden, Mark; Gough, Michael; Young, Kristina H. (2021). "Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer". OncoImmunology. 10 (1) 1900635. doi:10.1080/2162402X.2021.1900635. PMC 7993148. PMID 33796412.
  27. ↑ Lynch, Kevin T.; Young, Samuel J.; Meneveau, Max O.; Wages, Nolan A.; Engelhard, Victor H.; Slingluff, Craig L.; Mauldin, Ileana S. (2021). "Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma". Journal for ImmunoTherapy of Cancer. 9 (6) e002273. doi:10.1136/jitc-2020-002273. PMC 8190052. PMID 34103353.
  28. ↑ Deng, Shuxuan; Chen, Yanjie; Song, Bin (2025). "Tertiary lymphoid structures in cancer: spatiotemporal heterogeneity, immune orchestration, and translational opportunities". Journal of Hematology & Oncology. 18 (1): 97. doi:10.1186/s13045-025-01754-7. PMC 12606831. PMID 41219991.
  29. ↑ Figenschau, Stine L.; Fismen, Silje; Fenton, Kristin A.; Fenton, Christopher; Mortensen, Elin S. (2015). "Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients". BMC Cancer. 15 101. doi:10.1186/s12885-015-1116-1. PMC 4357183. PMID 25884667.
  30. ↑ Finkin, Shiri; Yuan, Dan; Stein, Ian (2015). "Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma". Nature Immunology. 16 (12): 1235–1244. doi:10.1038/ni.3290. PMC 4653079. PMID 26502405.
  31. ↑ Joshi, Nikhil S.; Akama-Garren, Elliot H.; Lu, Yisi; Lee, Da-Yae; Chang, Gregory P. (2015). "Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses". Immunity. 43 (3): 579–590. doi:10.1016/j.immuni.2015.08.006. PMC 4826619. PMID 26341400.
  32. ↑ Noort, Ae R.; van Zoest, Katinka P. M.; van Baarsen, Lisa G.; Maracle, Chrissta X.; Helder, Boy; Papazian, Natalie; Romera-Hernandez, Monica; Tak, Paul P.; Cupedo, Tom; Tas, Sander W. (2015). "Tertiary Lymphoid Structures in Rheumatoid Arthritis: NF-κB-Inducing Kinase-Positive Endothelial Cells as Central Players". American Journal of Pathology. 185 (7): 1935–1943. doi:10.1016/j.ajpath.2015.03.012. PMID 25963989.
  33. ↑ Dorraji, S. Esmaeil; Hovd, Aud-Malin K.; Kanapathippillai, Premasany; Bakland, Gunnstein; Eilertsen, Gro Østli; Figenschau, Stine L.; Fenton, Kristin A. (2018). "Mesenchymal stem cells and T cells in the formation of Tertiary Lymphoid Structures in Lupus Nephritis". Scientific Reports. 8 (1) 7861. Bibcode:2018NatSR...8.7861D. doi:10.1038/s41598-018-26265-z. PMC 5959845. PMID 29777158.
  34. ↑ Pontarini, Elena; Sciacca, Elisabetta; Grigoriadou, Sofia; Rivellese, Felice; Lucchesi, Davide; Fossati-Jimack, Liliane; Coleby, Rachel; Chowdhury, Farzana; Calcaterra, Francesca; Tappuni, Anwar; Lewis, Myles J.; Fabris, Martina (2021). "NKp30 Receptor Upregulation in Salivary Glands of Sjögren's Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment". Frontiers in Immunology. 12 706737. doi:10.3389/fimmu.2021.706737. PMC 8477027. PMID 34594326.
  35. ↑ Zhou, Shengru; Liu, Zhicui; Yuan, Huijie; Zhao, Xiaoqing; Zou, Yaru; Zheng, Jie; Pan, Meng (2020). "Autoreactive B Cell Differentiation in Diffuse Ectopic Lymphoid-Like Structures of Inflamed Pemphigus Lesions". Journal of Investigative Dermatology. 140 (2): 309–318.e8. doi:10.1016/j.jid.2019.07.717. PMID 31476317.
  36. ↑ Morille, Jérémy; Mandon, Marion; Rodriguez, Stéphane (2022). "Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature". Neurology: Neuroimmunology & Neuroinflammation. 9 (6) e200033. doi:10.1212/NXI.0000000000200033. PMC 9585484. PMID 36266053.
  37. ↑ Korpos, Éva; Kadri, Nadir; Loismann, Sophie; Findeisen, Clais R.; Arfuso, Frank; Burke, George W. III; Richardson, Sarah J.; Morgan, Noel G.; Bogdani, Marika; Pugliese, Alberto; Sorokin, Lydia (2021). "Identification and characterisation of tertiary lymphoid organs in human type 1 diabetes". Diabetologia. 64 (7): 1626–1641. doi:10.1007/s00125-021-05453-z. PMC 8187221. PMID 33912981.
  38. ↑ Epps, Simon J.; Coplin, Natalie; Luthert, Philip J.; Dick, Andrew D.; Coupland, Sarah E.; Nicholson, Lindsay B. (2020). "Features of ectopic lymphoid-like structures in human uveitis". Experimental Eye Research. 191 107901. doi:10.1016/j.exer.2019.107901. PMC 7029346. PMID 31877281.
  39. ↑ Graver, Jacoba C.; Boots, Annemieke M. H.; Haacke, Erlin A.; Diepstra, Arjan; Brouwer, Elisabeth; Sandovici, Maria (2019). "Massive B-Cell Infiltration and Organization Into Artery Tertiary Lymphoid Organs in the Aorta of Large Vessel Giant Cell Arteritis". Frontiers in Immunology. 10 83. doi:10.3389/fimmu.2019.00083. PMC 6361817. PMID 30761147.
  40. ↑ Maghrabi, Yazid; Hakamy, Sahar; Bahabri, Nizar; AlSobaei, Mohammed; Abuzinadah, Ahmad R.; Kurdi, Maher (2021). "Adult-type dermatomyositis with secondary lymphoid follicles harbouring reactive B-cells component". Neuromuscular Disorders. 31 (9): 881–885. doi:10.1016/j.nmd.2021.07.001. PMID 34407910.
  41. ↑ Dong, Yuanji; Wang, Ting; Wu, Huaxiang (2024). "Tertiary lymphoid structures in autoimmune diseases". Frontiers in Immunology. 14 1322035. doi:10.3389/fimmu.2023.1322035. PMC 10800951. PMID 38259436.
  42. ↑ Taniguchi, Keisuke; Yoshikawa, Takahisa; Yanagita, Motoko (2025). "The roles of tertiary lymphoid structures in orchestrating immune responses in peripheral organs". Inflammation and Regeneration. 45 (1): 28. doi:10.1186/s41232-025-00393-2. PMC 12486510. PMID 41029827.

Category:Immune system Category:Lymphatic system

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