Skip to main content

Advertisement

SpringerLink
Log in

Tertiary lymphoid structures in anticancer immunity

  • Review Article
  • Published:

From Nature Reviews Cancer

View current issue Sign up to alerts

Abstract

Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates where adaptive antitumour cellular and humoral responses can be elaborated. Initially described in non-small cell lung cancer as functional immune lymphoid structures associated with better clinical outcome, TLS have also been found in many other carcinomas, as well as melanomas and sarcomas, and associated with improved response to immunotherapy. The manipulation of TLS as a therapeutic strategy is now coming of age owing to the likely role of TLS in the improved survival of patients with cancer receiving immune checkpoint inhibitor treatment. TLS have also garnered considerable interest as a predictive biomarker of the response to antitumour therapies, including immune checkpoint blockade and, possibly, chemotherapy. However, several important questions still remain regarding the definition of TLS in terms of both their cellular composition and functions. Here, we summarize the current views on the composition of TLS at different stages of their development. We also discuss the role of B cells and T cells associated with TLS and their dialogue in mounting antibody and cellular antitumour responses, as well as some of the various mechanisms that negatively regulate antitumour activity of TLS. The prognostic value of TLS to the clinical outcome of patients with cancer and the relationship between TLS and the response to therapy are then addressed. Finally, we present some preclinical evidence that favours the idea that manipulating the formation and function of TLS could lead to a potent next-generation cancer immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: The three main states of tertiary lymphoid structures.
Fig. 2: Representative mature tertiary lymphoid structure from a patient with non-small cell lung cancer.
Fig. 3: Main effector and regulatory mechanisms initiated in tertiary lymphoid structures.
Fig. 4: Therapeutic strategies to target tertiary lymphoid structures.

Similar content being viewed by others

References

  1. Rosenberg, S. A., Spiess, P. & Lafreniere, R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233, 1318–1321 (1986).

    Article  CAS  PubMed  Google Scholar 

  2. Hérin, M. et al. Production of stable cytolytic T-cell clones directed against autologous human melanoma. Int. J. Cancer 39, 390–396 (1987).

    Article  PubMed  Google Scholar 

  3. Gross, G., Waks, T. & Eshhar, Z. Expression of immunoglobulin–T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86, 10024–10028 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Harrison, J. C., Dean, P. J., el-Zeky, F. & Vander Zwaag, R. Impact of the Crohn’s-like lymphoid reaction on staging of right-sided colon cancer: results of multivariate analysis. Hum. Pathol. 26, 31–38 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Wada, Y., Nakashima, O., Kutami, R., Yamamoto, O. & Kojiro, M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 27, 407–414 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Griss, J. et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10, 4186 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Meylan, M. et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity 55, 527–541.e5 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. Patil, N. S. et al. Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer. Cancer Cell 40, 289–300.e4 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Garaud, S. et al. Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight 5, e129641 (2019).

    Article  PubMed  Google Scholar 

  10. Nzula, S., Going, J. J. & Stott, D. I. Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas. Cancer Res. 63, 3275–3280 (2003).

    CAS  PubMed  Google Scholar 

  11. Coronella, J. A. et al. Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J. Immunol. 169, 1829–1836 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Pagès, F. et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654–2666 (2005).

    Article  PubMed  Google Scholar 

  13. Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Ruddle, N. H. Lymphoid neo-organogenesis: lymphotoxin’s role in inflammation and development. Immunol. Res. 19, 119–125 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Baddoura, F. K. et al. Lymphoid neogenesis in murine cardiac allografts undergoing chronic rejection. Am. J. Transplant. 5, 510–516 (2005).

    Article  PubMed  Google Scholar 

  16. Dieu-Nosjean, M.-C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26, 4410–4417 (2008). This seminal paper reports the presence and correlation of TLS with better clinical outcomes in patients with solid tumours.

    Article  CAS  PubMed  Google Scholar 

  17. Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Coppola, D. et al. Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. Am. J. Pathol. 179, 37–45 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sofopoulos, M. et al. The prognostic significance of peritumoral tertiary lymphoid structures in breast cancer. Cancer Immunol. Immunother. 68, 1733–1745 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kroeger, D. R., Milne, K. & Nelson, B. H. Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer. Clin. Cancer Res. 22, 3005–3015 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Ruffin, A. T. et al. B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma. Nat. Commun. 12, 3349 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hiraoka, N. et al. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br. J. Cancer 112, 1782–1790 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pfannstiel, C. et al. The tumor immune microenvironment drives a prognostic relevance that correlates with bladder cancer subtypes. Cancer Immunol. Res. 7, 923–938 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Messina, J. L. et al. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci. Rep. 2, 765 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. Hennequin, A. et al. Tumor infiltration by Tbet+ effector T cells and CD20+ B cells is associated with survival in gastric cancer patients. OncoImmunology 5, e1054598 (2016).

    Article  PubMed  Google Scholar 

  27. Ruddle, N. H. & Akirav, E. M. Secondary lymphoid organs: responding to genetic and environmental cues in ontogeny and the immune response. J. Immunol. 183, 2205–2212 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Thompson, E. C. Focus issue: structure and function of lymphoid tissues. Trends Immunol. 33, 255 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Kratz, A., Campos-Neto, A., Hanson, M. S. & Ruddle, N. H. Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J. Exp. Med. 183, 1461–1472 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).

    Article  PubMed  Google Scholar 

  31. Roozendaal, R. & Mebius, R. E. Stromal cell–immune cell interactions. Annu. Rev. Immunol. 29, 23–43 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Randall, T. D., Carragher, D. M. & Rangel-Moreno, J. Development of secondary lymphoid organs. Annu. Rev. Immunol. 26, 627–650 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Rangel-Moreno, J. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12, 639–646 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, K. et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 41, 1052–1063 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Figenschau, S. L. et al. ICAM1 expression is induced by proinflammatory cytokines and associated with TLS formation in aggressive breast cancer subtypes. Sci. Rep. 8, 11720 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Le Hir, M. et al. Differentiation of follicular dendritic cells and full antibody responses require tumor necrosis factor receptor-1 signaling. J. Exp. Med. 183, 2367–2372 (1996).

    Article  PubMed  Google Scholar 

  39. Blanchard, L. & Girard, J.-P. High endothelial venules (HEVs) in immunity, inflammation and cancer. Angiogenesis 24, 719–753 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maeda, K., Kosco-Vilbois, M. H., Burton, G. F., Szakal, A. K. & Tew, J. G. Expression of the intercellular adhesion molecule-1 on high endothelial venules and on non-lymphoid antigen handling cells: interdigitating cells, antigen transporting cells and follicular dendritic cells. Cell Tissue Res. 279, 47–54 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Vella, G., Hua, Y. & Bergers, G. High endothelial venules in cancer: regulation, function, and therapeutic implication. Cancer Cell 41, 527–545 (2023).

    Article  CAS  PubMed  Google Scholar 

  42. Bao, Y., Tong, C. & Xiong, X. CXCL3: a key player in tumor microenvironment and inflammatory diseases. Life Sci. 348, 122691 (2024).

    Article  CAS  PubMed  Google Scholar 

  43. Lynch, K. T. et al. Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma. J. Immunother. Cancer 9, e002273 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Siliņa, K. et al. Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma. Cancer Res. 78, 1308–1320 (2018).

    Article  PubMed  Google Scholar 

  45. Kasikova, L. et al. Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer. Nat. Commun. 15, 2528 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Workel, H. H. et al. A transcriptionally distinct CXCL13+CD103+CD8+ T-cell population is associated with B-cell recruitment and neoantigen load in human cancer. Cancer Immunol. Res. 7, 784–796 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Ng, K. W. et al. Antibodies against endogenous retroviruses promote lung cancer immunotherapy. Nature 616, 563–573 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu, W. et al. An immune cell map of human lung adenocarcinoma development reveals an anti-tumoral role of the TFH-dependent tertiary lymphoid structure. Cell Rep. Med. 5, 101448 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Martínez-Riaño, A. et al. Long-term retention of antigens in germinal centers is controlled by the spatial organization of the follicular dendritic cell network. Nat. Immunol. 24, 1281–1294 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Goc, J. et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a TH1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 74, 705–715 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Gu-Trantien, C. et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Invest. 123, 2873–2892 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Joshi, N. S. et al. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43, 579–590 (2015). This paper shows that Treg cells in tumour-associated TLS suppress antitumour T cell responses in a mouse model of lung cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bugatti, M. et al. A population of TIM4+FOLR2+ macrophages localized in tertiary lymphoid structures correlates to an active immune infiltrate across several cancer types. Cancer Immunol. Res. 10, 1340–1353 (2022).

    Article  CAS  PubMed  Google Scholar 

  54. Acton, S. E., Onder, L., Novkovic, M., Martinez, V. G. & Ludewig, B. Communication, construction, and fluid control: lymphoid organ fibroblastic reticular cell and conduit networks. Trends Immunol. 42, 782–794 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. Liu, Y.-J. et al. Follicular dendritic cells specifically express the long CR2/CD21 isoform. J. Exp. Med. 185, 165–170 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kinker, G. S. et al. Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas. Gut 72, 1927–1941 (2023).

    Article  CAS  PubMed  Google Scholar 

  57. Grootveld, A. K. et al. Apoptotic cell fragments locally activate tingible body macrophages in the germinal center. Cell 186, 1144–1161.e18 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. de Chaisemartin, L. et al. Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res. 71, 6391–6399 (2011).

    Article  PubMed  Google Scholar 

  59. Sleeman, J. P. & Thiele, W. Tumor metastasis and the lymphatic vasculature. Int. J. Cancer 125, 2747–2756 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. GeurtsvanKessel, C. H. et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J. Exp. Med. 206, 2339–2349 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Barone, F. et al. IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. Proc. Natl Acad. Sci. USA 112, 11024–11029 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Rodriguez, A. B. et al. Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts. Cell Rep. 36, 109422 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nayar, S. et al. Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction. Commun. Biol. 5, 413 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Engelhard, V. H. et al. Immune cell infiltration and tertiary lymphoid structures as determinants of antitumor immunity. J. Immunol. 200, 432–442 (2018).

    Article  CAS  PubMed  Google Scholar 

  66. Farr, A. G. et al. Characterization and cloning of a novel glycoprotein expressed by stromal cells in T-dependent areas of peripheral lymphoid tissues. J. Exp. Med. 176, 1477–1482 (1992).

    Article  CAS  PubMed  Google Scholar 

  67. Herzog, B. H. et al. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 502, 105–109 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nejman, D. et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368, 973 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fu, A. et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell 185, 1356–1372.e26 (2022).

    Article  CAS  PubMed  Google Scholar 

  70. Overacre-Delgoffe, A. E. et al. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity 54, 2812–2824.e4 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Silva-Sanchez, A., Randall, T. D. & Meza-Perez, S. Tertiary lymphoid structures among the world of noncanonical ectopic lymphoid organizations. Methods Mol. Biol. 1845, 1–15 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Posch, F. et al. Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. Oncoimmunology 7, e1378844 (2018).

    Article  PubMed  Google Scholar 

  73. Wengner, A. M. et al. CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum. 56, 3271–3283 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Fleige, H. et al. IL-17-induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs. J. Exp. Med. 211, 643–651 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Luther, S. A., Lopez, T., Bai, W., Hanahan, D. & Cyster, J. G. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12, 471–481 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10, 927–934 (2004). This study reports that mice lacking a spleen, lymph nodes and Peyer’s patches but with induced bronchus-associated lymphoid tissue generate protective primary B cell and T cell responses to influenza.

    Article  CAS  PubMed  Google Scholar 

  77. Shu, D. H. et al. Immune landscape of tertiary lymphoid structures in hepatocellular carcinoma (HCC) treated with neoadjuvant immune checkpoint blockade. Preprint at bioRxiv https://doi.org/10.1101/2023.10.16.562104 (2023).

  78. Riffard, C. et al. Absence of sympathetic innervation hampers the generation of tertiary lymphoid structures upon acute lung inflammation. Sci. Rep. 14, 11749 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shibasaki, Y. et al. Cold-blooded vertebrates evolved organized germinal center-like structures. Sci. Immunol. 8, eadf1627 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Asrir, A. et al. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell 40, 318–334.e9 (2022).

    Article  CAS  PubMed  Google Scholar 

  81. Fridman, W. H., Sibéril, S., Pupier, G., Soussan, S. & Sautès-Fridman, C. Activation of B cells in tertiary lymphoid structures in cancer: anti-tumor or anti-self? Semin. Immunol. 65, 101703 (2023).

    Article  CAS  PubMed  Google Scholar 

  82. Huang, Y. et al. Improving immune-vascular crosstalk for cancer immunotherapy. Nat. Rev. Immunol. 18, 195–203 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jain, R. K. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 50, 814s–819s (1990).

    CAS  PubMed  Google Scholar 

  84. Boissonnas, A., Fetler, L., Zeelenberg, I. S., Hugues, S. & Amigorena, S. In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J. Exp. Med. 204, 345–356 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Platonova, S. et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 71, 5412–5422 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Pontarini, E. et al. NK cell recruitment in salivary glands provides early viral control but is dispensable for tertiary lymphoid structure formation. J. Leukoc. Biol. 105, 589–602 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. Moyron-Quiroz, J. E. et al. Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity 25, 643–654 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Blümich, S., Zdimerova, H., Münz, C., Kipar, A. & Pellegrini, G. Human CD34+ hematopoietic stem cell-engrafted NSG mice: morphological and immunophenotypic features. Vet. Pathol. 58, 161–180 (2021).

    Article  PubMed  Google Scholar 

  90. Küçükköse, E. et al. Modeling resistance of colorectal peritoneal metastases to immune checkpoint blockade in humanized mice. J. Immunother. Cancer 10, e005345 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Cipponi, A. et al. Neogenesis of lymphoid structures and antibody responses occur in human melanoma metastases. Cancer Res. 72, 3997–4007 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Germain, C. et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am. J. Respir. Crit. Care Med. 189, 832–844 (2014). This study shows that B cell density is a prognostic biomarker for the survival of patients with NSCLC and is directly associated with TLS providing a protective antitumour B cell response.

    Article  CAS  PubMed  Google Scholar 

  93. J Gunderson, A. et al. Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer. Oncoimmunology 10, 1900635 (2021).

    Article  PubMed  Google Scholar 

  94. Chen, J. et al. Single-cell transcriptome and antigen-immunoglobin analysis reveals the diversity of B cells in non-small cell lung cancer. Genome Biol. 21, 152 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Xia, J. et al. Single-cell landscape and clinical outcomes of infiltrating B cells in colorectal cancer. Immunology 168, 135–151 (2023).

    Article  CAS  PubMed  Google Scholar 

  96. Montfort, A. et al. A strong B-cell response is part of the immune landscape in human high-grade serous ovarian metastases. Clin. Cancer Res. 23, 250–262 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Kotlan, B. et al. Immunoglobulin variable regions usage by B-lymphocytes infiltrating a human breast medullary carcinoma. Immunol. Lett. 65, 143–151 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Kotlan, B. et al. Novel ganglioside antigen identified by B cells in human medullary breast carcinomas: the proof of principle concerning the tumor-infiltrating B lymphocytes. J. Immunol. 175, 2278–2285 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Roumenina, L. T. et al. Tumor cells hijack macrophage-produced complement C1q to promote tumor growth. Cancer Immunol. Res. 7, 1091–1105 (2019).

    Article  CAS  PubMed  Google Scholar 

  100. Elsner, R. A. & Shlomchik, M. J. Germinal center and extrafollicular B cell responses in vaccination, immunity, and autoimmunity. Immunity 53, 1136–1150 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Biswas, S. et al. IgA transcytosis and antigen recognition govern ovarian cancer immunity. Nature 591, 464–470 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Garaud, S. et al. Antigen specificity and clinical significance of IgG and IgA autoantibodies produced in situ by tumor-infiltrating B cells in breast cancer. Front. Immunol. 9, 2660 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Yasuda, M. et al. Antigens recognized by IgG derived from tumor-infiltrating B lymphocytes in human lung cancer. Anticancer. Res. 26, 3607–3611 (2006).

    CAS  PubMed  Google Scholar 

  104. Mazor, R. D. et al. Tumor-reactive antibodies evolve from non-binding and autoreactive precursors. Cell 185, 1208–1222.e21 (2022).

    Article  CAS  PubMed  Google Scholar 

  105. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020). Together with Petitprez et al. (2020) and Helmink et al. (2020), this paper supports a role for B cells within TLS in the response to ICB.

    Article  CAS  PubMed  Google Scholar 

  107. Teillaud, J.-L. & Dieu-Nosjean, M.-C. Intratumoral plasma cells: more than a predictive marker of response to anti-PD-L1 treatment in lung cancer? Cancer Cell 40, 240–243 (2022).

    Article  CAS  PubMed  Google Scholar 

  108. Schultze, J. L. et al. CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J. Clin. Invest. 100, 2757–2765 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hong, S. et al. B cells are the dominant antigen-presenting cells that activate naive CD4+ T cells upon immunization with a virus-derived nanoparticle antigen. Immunity 49, 695–708.e4 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. Carrasco, Y. R. & Batista, F. D. B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity 27, 160–171 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Harris, D. P. et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat. Immunol. 1, 475–482 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Tumanov, A. et al. Distinct role of surface lymphotoxin expressed by B cells in the organization of secondary lymphoid tissues. Immunity 17, 239–250 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Vazquez, M. I., Catalan-Dibene, J. & Zlotnik, A. B cells responses and cytokine production are regulated by their immune microenvironment. Cytokine 74, 318–326 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Laumont, C. M. & Nelson, B. H. B cells in the tumor microenvironment: multi-faceted organizers, regulators, and effectors of anti-tumor immunity. Cancer Cell 41, 466–489 (2023).

    Article  CAS  PubMed  Google Scholar 

  115. Dutertre, C.-A. A new step in understanding mouse cDC ontogeny. Nat. Immunol. 25, 383–384 (2024).

    Article  CAS  PubMed  Google Scholar 

  116. Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhu, W. et al. A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+ T cell receptor repertoire clonality. Oncoimmunology 4, e1051922 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Lee, Y. et al. Recruitment and activation of naive T cells in the islets by lymphotoxin β receptor-dependent tertiary lymphoid structure. Immunity 25, 499–509 (2006). This study reports the critical role of the LIGHT–LTβR axis in the development and maintenance of TLS at sites of chronic autoimmune inflammation at the onset of diabetes.

    Article  CAS  PubMed  Google Scholar 

  119. Barone, F. et al. Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inflammation. Front. Immunol. 7, 477 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Peske, J. D. et al. Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Nat. Commun. 6, 7114 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Schumacher, T. N. & Thommen, D. S. Tertiary lymphoid structures in cancer. Science 375, 6576 (2022).

    Article  Google Scholar 

  122. Boissonnas, A. et al. Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. Immunity 32, 266–278 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Cruz de Casas, P., Knöpper, K., Dey Sarkar, R. & Kastenmüller, W. Same yet different — how lymph node heterogeneity affects immune responses. Nat. Rev. Immunol. 24, 358–374 (2023).

    Article  PubMed  Google Scholar 

  124. Ishigami, E. et al. Coexistence of regulatory B cells and regulatory T cells in tumor-infiltrating lymphocyte aggregates is a prognostic factor in patients with breast cancer. Breast Cancer 26, 180–189 (2019).

    Article  PubMed  Google Scholar 

  125. Devi-Marulkar, P. et al. Regulatory T cells infiltrate the tumor-induced tertiary lymphoïd structures and are associated with poor clinical outcome in NSCLC. Commun. Biol. 5, 1–16 (2022).

    Article  Google Scholar 

  126. Germain, C. et al. Tertiary lymphoid structure-B cells narrow regulatory T cells impact in lung cancer patients. Front. Immunol. 12, 626776 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Noël, G. et al. Functional TH1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity. J. Clin. Invest. 131, e139905 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Cottrell, T. R. et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann. Oncol. 29, 1853–1860 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. van Dijk, N. et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat. Med. 26, 1839–1844 (2020).

    Article  PubMed  Google Scholar 

  130. Truxova, I. et al. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients. J. Immunother. Cancer 6, 139 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Ding, G.-Y. et al. Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma. J. Hepatol. 76, 608–618 (2022).

    Article  CAS  PubMed  Google Scholar 

  132. Horeweg, N. et al. Tertiary lymphoid structures critical for prognosis in endometrial cancer patients. Nat. Commun. 13, 1373 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bruni, D., Angell, H. K. & Galon, J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat. Rev. Cancer 20, 662–680 (2020).

    Article  CAS  PubMed  Google Scholar 

  134. Dieu-Nosjean, M.-C. Tumor-associated tertiary lymphoid structures: a cancer biomarker and a target for next-generation immunotherapy. Adv. Exp. Med. Biol. 1329, 51–68 (2021).

    Article  CAS  PubMed  Google Scholar 

  135. Merali, N. et al. Impact of tertiary lymphoid structures on prognosis and therapeutic response in pancreatic ductal adenocarcinoma. HPB 26, 873–894 (2024).

    Article  PubMed  Google Scholar 

  136. Masuda, T. et al. Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer. J. Immunother. Cancer 10, e003883 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  137. van Rijthoven, M. et al. Multi-resolution deep learning characterizes tertiary lymphoid structures and their prognostic relevance in solid tumors. Commun. Med. 4, 5 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Calderaro, J. et al. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J. Hepatol. 70, 58–65 (2019).

    Article  PubMed  Google Scholar 

  139. Jia, W. et al. Protective effect of tertiary lymphoid structures against hepatocellular carcinoma: new findings from a genetic perspective. Front. Immunol. 13, 1007426 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lin, Z. et al. Pan-cancer analysis of genomic properties and clinical outcome associated with tumor tertiary lymphoid structure. Sci. Rep. 10, 21530 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Cillo, A. R. et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity 52, 183–199.e9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Pagliarulo, F. et al. Molecular, immunological, and clinical features associated with lymphoid neogenesis in muscle invasive bladder cancer. Front. Immunol. 12, 793992 (2021).

    Article  CAS  PubMed  Google Scholar 

  143. Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Maldonado, L. et al. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci. Transl Med. 6, 221ra13 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Sweeney, K. J. et al. Tertiary lymphoid structures with overlapping histopathologic features of cutaneous marginal zone lymphoma during neoadjuvant cemiplimab therapy are associated with antitumor response. J. Cutan. Pathol. 48, 674–679 (2021).

    Article  PubMed  Google Scholar 

  146. Cascone, T. et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nat. Med. 29, 593–604 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lu, Y. et al. Complement signals determine opposite effects of B cells in chemotherapy-induced immunity. Cell 180, 1081–1097.e24 (2020).

    Article  CAS  PubMed  Google Scholar 

  148. Bruchard, M. et al. Recruitment and activation of type 3 innate lymphoid cells promote antitumor immune responses. Nat. Immunol. 23, 262–274 (2022).

    Article  CAS  PubMed  Google Scholar 

  149. Remark, R. et al. Immune contexture and histological response after neoadjuvant chemotherapy predict clinical outcome of lung cancer patients. Oncoimmunology 5, e1255394 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Morcrette, G. et al. APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. OncoImmunology 8, e1583547 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Kroemer, G., Galassi, C., Zitvogel, L. & Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 23, 487–500 (2022).

    Article  CAS  PubMed  Google Scholar 

  152. Ascierto, P. A. et al. The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment. J. Transl Med. 11, 54 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Liu, Z., Meng, X., Tang, X., Zou, W. & He, Y. Intratumoral tertiary lymphoid structures promote patient survival and immunotherapy response in head neck squamous cell carcinoma. Cancer Immunol. Immunother. 72, 1505–1521 (2023).

    Article  CAS  PubMed  Google Scholar 

  154. Gao, J. et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat. Med. 26, 1845–1851 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Shang, T. et al. Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma. Front. Immunol. 14, 1166497 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Voabil, P. et al. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nat. Med. 27, 1250–1261 (2021).

    Article  CAS  PubMed  Google Scholar 

  157. Italiano, A. et al. Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort. Nat. Med. 28, 1199–1206 (2022).

    Article  CAS  PubMed  Google Scholar 

  158. Vanhersecke, L. et al. Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression. Nat. Cancer 2, 794–802 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Groeneveld, C. S. et al. Tertiary lymphoid structures marker CXCL13 is associated with better survival for patients with advanced-stage bladder cancer treated with immunotherapy. Eur. J. Cancer 148, 181–189 (2021).

    Article  CAS  PubMed  Google Scholar 

  160. Wu, Z. et al. CD20+CD22+ADAM28+ B cells in tertiary lymphoid structures promote immunotherapy response. Front. Immunol. 13, 865596 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lee, H. J. et al. Prognostic significance of tumor-infiltrating lymphocytes and the tertiary lymphoid structures in HER2-positive breast cancer treated with adjuvant trastuzumab. Am. J. Clin. Pathol. 144, 278–288 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Lin, Q. et al. Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors. Oncoimmunology 9, 1747339 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Wang, Q. et al. Single-cell transcriptome sequencing of B-cell heterogeneity and tertiary lymphoid structure predicts breast cancer prognosis and neoadjuvant therapy efficacy. Clin. Transl Med. 13, e1346 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Emens, L. A. et al. Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur. J. Cancer 81, 116–129 (2017).

    Article  CAS  PubMed  Google Scholar 

  165. Schrama, D. et al. Targeting of lymphotoxin-ɑ to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14, 111–121 (2001). This paper describes an antibody–LTα fusion protein that induces a protective antitumour response through the formation of a lymphoid-like structure in the tumour microenvironment.

    Article  CAS  PubMed  Google Scholar 

  166. Tang, H. et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell 29, 285–296 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Johansson-Percival, A. et al. De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors. Nat. Immunol. 18, 1207–1217 (2017). This study reports that targeting LIGHT to tumour vessels via a vascular-targeting peptide enables modulation of the angiogenic vasculature and the induction of TLS.

    Article  CAS  PubMed  Google Scholar 

  168. Ramachandran, M. et al. Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma. Cancer Cell 41, 1134–1151 (2023).

    Article  CAS  PubMed  Google Scholar 

  169. Chelvanambi, M., Fecek, R. J., Taylor, J. L. & Storkus, W. J. STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment. J. Immunother. Cancer 9, e001906 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  170. van Hooren, L. et al. Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. Nat. Commun. 12, 4127 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Delvecchio, F. R. et al. Pancreatic cancer chemotherapy is potentiated by induction of tertiary lymphoid structures in mice. Cell. Mol. Gastroenterol. Hepatol. 41, 1134–1151.e10 (2021).

    Google Scholar 

  172. Johansson-Percival, A. & Ganss, R. Therapeutic induction of tertiary lymphoid structures in cancer through stromal remodeling. Front. Immunol. 12, 674375 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Cupedo, T., Jansen, W., Kraal, G. & Mebius, R. E. Induction of secondary and tertiary lymphoid structures in the skin. Immunity 21, 655–667 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Chaurio, R. A. et al. TGF-β-mediated silencing of genomic organizer SATB1 promotes TFH cell differentiation and formation of intra-tumoral tertiary lymphoid structures. Immunity 55, 115–128.e9 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. van Hooren, L. et al. CD103+ regulatory T cells underlie resistance to radio-immunotherapy and impair CD8+ T cell activation in glioblastoma. Nat. Cancer 4, 665–681 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Zhang, N. et al. LIGHT/TNFSF14 promotes CAR-T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment. Mol. Ther. 31, 2575–2590 (2023).

    Article  CAS  PubMed  Google Scholar 

  177. Wang, G. et al. An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses. Nat. Commun. 11, 1395 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Houel, A., Foloppe, J. & Dieu-Nosjean, M.-C. Harnessing the power of oncolytic virotherapy and tertiary lymphoid structures to amplify antitumor immune responses in cancer patients. Semin. Immunol. 69, 101796 (2023).

    Article  CAS  PubMed  Google Scholar 

  179. Clubb, J. H. A. et al. Adenovirus encoding tumor necrosis factor ɑ and interleukin 2 induces a tertiary lymphoid structure signature in immune checkpoint inhibitor refractory head and neck cancer. Front. Immunol. 13, 794251 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. He, T. et al. Oncolytic adenovirus promotes vascular normalization and nonclassical tertiary lymphoid structure formation through STING-mediated DC activation. Oncoimmunology 11, 2093054 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Rosato, P. C. et al. Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nat. Commun. 10, 567 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Kim, S.-I. et al. Recombinant orthopoxvirus primes colon cancer for checkpoint inhibitor and cross-primes T cells for antitumor and antiviral immunity. Mol. Cancer Ther. 20, 173–182 (2021).

    Article  CAS  PubMed  Google Scholar 

  183. Russell, S. J. & Barber, G. N. Oncolytic viruses as antigen agnostic tumor vaccines. Cancer Cell 33, 599–605 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  CAS  PubMed  Google Scholar 

  185. Ren, X., Lin, S., Guan, F. & Kang, H. Glycosylation targeting: a paradigm shift in cancer immunotherapy. Int. J. Biol. Sci. 20, 2607–2621 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Schoen, R. E. et al. Randomized, double-blind, placebo-controlled trial of MUC1 peptide vaccine for prevention of recurrent colorectal adenoma. Clin. Cancer Res. 29, 1678–1688 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Das, R. et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J. Clin. Invest. 128, 715–720 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Ghosh, N., Chan, K. K., Jivanelli, B. & Bass, A. R. Autoantibodies in patients with immune-related adverse events from checkpoint inhibitors: a systematic literature review. J. Clin. Rheumatol. 28, e498–e505 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Zhang, J., Huang, D., Saw, P. E. & Song, E. Turning cold tumors hot: from molecular mechanisms to clinical applications. Trends Immunol. 43, 523–545 (2022).

    Article  CAS  PubMed  Google Scholar 

  190. Dalmau, J. & Rosenfeld, M. R. Paraneoplastic syndromes of the CNS. Lancet Neurol. 7, 327–340 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Thompson, E. D., Enriquez, H. L., Fu, Y.-X. & Engelhard, V. H. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J. Exp. Med. 207, 1791–1804 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Sun, X. et al. Maturation and abundance of tertiary lymphoid structures are associated with the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer. J. Immunother. Cancer 10, e005531 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Giraldo, N. A. et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin. Cancer Res. 21, 3031–3040 (2015).

    Article  CAS  PubMed  Google Scholar 

  194. Le Rochais, M. et al. Deciphering the maturation of tertiary lymphoid structures in cancer and inflammatory diseases of the digestive tract using imaging mass cytometry. Front. Immunol. 14, 1147480 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Xu, A. M. et al. Spatiotemporal architecture of immune cells and cancer-associated fibroblasts in high-grade serous ovarian carcinoma. Sci. Adv. 10, eadk8805 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Martinet, L. et al. High endothelial venule blood vessels for tumor-infiltrating lymphocytes are associated with lymphotoxin β-producing dendritic cells in human breast cancer. J. Immunol. 191, 2001–2008 (2013).

    Article  CAS  PubMed  Google Scholar 

  197. Li, J.-P. et al. PD-1+CXCR5–CD4+ TH-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma. J. Immunother. Cancer 9, e002101 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Rangel-Moreno, J. et al. The development of inducible bronchus associated lymphoid tissue (iBALT) is dependent on IL-17. Nat. Immunol. 12, 639–646 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Sarti Kinker, G. & da Silva Medina, T. Tertiary lymphoid structures as hubs of antitumour immunity. Nat. Rev. Cancer 23, 803 (2023).

    Article  CAS  PubMed  Google Scholar 

  200. Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 184, 4734–4752.e20 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Deryugina, E. I. & Quigley, J. P. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biol. 44–46, 94–112 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Prizant, H. et al. CXCL10+ peripheral activation niches couple preferred sites of TH1 entry with optimal APC encounter. Cell Rep. 36, 109523 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. He, S. et al. Starfysh integrates spatial transcriptomic and histologic data to reveal heterogeneous tumor-immune hubs. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02173-8 (2024).

  205. Chen, J. H. et al. Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy. Nat. Immunol. 25, 644–658 (2024).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of the authors was supported by Institut National de la Santé et de la Recherche Médicale (Inserm), Sorbonne University, the Fondation pour la recherche sur le cancer (ARC) (PJA 20191209801, PGA 2023110007351 to M.-C.D.-N.), the CARPEM (Cancer Research for Personalized Medicine Program) of the Sites Intégrés de Recherche sur le cancer (SIRIC), Institut National du Cancer (INCa-DGOS_10888 to M.-C.D.-N.) and AstraZeneca (to M.-C.D.-N.).

Author information

Authors and Affiliations

  1. Sorbonne University UMRS1135, Paris, France

    Jean-Luc Teillaud, Ana Houel, Marylou Panouillot, Clémence Riffard & Marie-Caroline Dieu-Nosjean

  2. Inserm U1135, Paris, France

    Jean-Luc Teillaud, Ana Houel, Marylou Panouillot, Clémence Riffard & Marie-Caroline Dieu-Nosjean

  3. Center of Immunology and Microbial Infections (Cimi), Faculty of Health, Paris, France

    Jean-Luc Teillaud, Ana Houel, Marylou Panouillot, Clémence Riffard & Marie-Caroline Dieu-Nosjean

  4. Transgene, Illkirch-Graffenstaden, France

    Ana Houel

  5. Sanofi, Vitry-sur-Seine, France

    Marylou Panouillot

Authors
  1. Jean-Luc Teillaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Houel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marylou Panouillot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Clémence Riffard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie-Caroline Dieu-Nosjean
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article. M.-C.D.-N. and J.-L.T. contributed substantially to discussion of the content. All authors wrote the article. M.-C.D.-N. and J.-L.T. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Marie-Caroline Dieu-Nosjean.

Ethics declarations

Competing interests

M.-C.D.-N. and J.-L.T. are named as inventors on several patents related to tertiary lymphoid structures (TLS) (EP2013/051047, EU 3341732, WO PCT/EP2022/052984) and antibody engineering (EP 3 187 505 B1; EP1824887 B1). M.-C.D.-N. is a consultant at Iteos Therapeutics. A.H. and M.P. received doctoral fellowships from the Association Nationale de la Recherche et de la Technologie (ANRT), and are employees of Transgene and Sanofi, respectively. C.R. received a doctoral fellowship from La Ligue contre le Cancer.

Peer review

Peer review information

Nature Reviews Cancer thanks Karina Silina and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Activation-induced cytidine deaminase

(AID). A mutator enzyme that initiates somatic hypermutation and is required for affinity maturation of antibodies. It deaminates cytidine to uracil on DNA, creating U:G mismatches, leading to point mutations upon repair in the DNA of variable domains and, hence, leading to sequence diversity of antibodies expressed by B cells.

Affinity maturation

The process occurring in germinal centres by which specific antibodies produced during secondary responses induced by antigenic rechallenge dramatically increase their average affinity for the antigen. It results from somatic hypermutation in the DNA of variable domains followed by the positive selection of B cells expressing mutated antibodies with the highest affinity for the antigen.

Class switch recombination

Also known as class switching. A B cell-specific DNA-rearrangement reaction that exchanges the expressed immunoglobulin heavy-chain constant-region gene (CH) from Cμ to another downstream CH gene. It results in the production of antibodies belonging to novel immunoglobulin classes (immunoglobulin G (IgG), IgA or IgE) with effector functions largely different from those of IgM.

Dark (Ki67+) zone of germinal centres

Containing large and mitotically active CXCR4+ B cells called centroblasts, the location of the antigen-driven selection of proliferating B cells.

Fibroblastic reticular cells

(FRCs). Heterogeneous stromal cells that control the micro-architecture of lymphoid organs. They give lymphoid organs the flexibility to stretch and contract to accommodate the recruitment of naive lymphocytes during an immune response. Their podoplanin (PDPN)-dependent contractility is inhibited by the influx of C-type lectin-like receptor 2 (CLEC2)+ dendritic cells (DCs) into lymphoid organs.

Follicular dendritic cells

(FDCs). Non-haematopoietic cells of stromal origin located within the B cell follicles and germinal centres of lymphoid organs. Distinct from the classical bone marrow-derived dendritic cells (DCs), they store and present antigens to B cells and are essential for germinal centre formation and maintenance.

Follicular regulatory T cells

(TFR cells). Cells representing a subset of germinal centre-residing regulatory T cells (Treg cells) and constitutively expressing the transcription factor forkhead box protein P3 (FOXP3). They have been proposed to be regulators of germinal centre formation, antigenic specificity, the emergence of autoreactive B cell clones and switching to various immunoglobulin classes.

Germinal centres

Structures which develop in the B cell follicles of secondary lymphoid organs (SLO) and tertiary lymphoid structures (TLS) and are the site where antigen-activated B cells proliferate, undergo somatic hypermutation in their immunoglobulin genes, and are subjected to class switch recombination and affinity-driven selection to produce high-affinity antibodies.

High endothelial venules

(HEVs). Post-capillary venules adapted for immune cell trafficking to secondary lymphoid organs (SLO) and tertiary lymphoid structures (TLS). They promote antitumour immunity by recruiting, for example, naive lymphocytes into tumours, especially in the context of treatment with immune checkpoint inhibitors.

Immune complexes

Molecular complexes where antibodies and antigens are bound together through non-covalent interactions. They exhibit various properties depending on their size, immunoglobulin class content and solubility. As examples, they can trigger activation of the classical complement pathway, or provoke immune cell activation or inhibition following binding to Fc receptors expressed by various immune and non-immune cells. They can also be associated with deleterious clinical effects following kidney or vascular deposition.

Light (CD21+) zone of germinal centres

Contain small and poorly proliferative CD21+ B cells called centrocytes which strongly express CD83 and CD86.

Lymphoid tissue inducer (LTi) cells

Heterogeneous haematopoietic cells that produce cytokines (that is, lymphotoxin α1β2 (LTα1β2), tumour necrosis factor (TNF), LIGHT and TRANCE (also known as TNFSF11A)) that stimulate the production of chemokines (that is, CC-chemokine ligand 19 (CCL19), CCL21 and CXC-chemokine ligand 13 (CXCL13)) and the expression of adhesion molecules (that is, vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1) and E-selectin) by stromal cells called lymphoid tissue organizer (LTo) cells.

Lymphoid tissue organizer (LTo) cells

Mesenchymal stromal cells that are activated by cytokines produced by lymphoid tissue inducer (LTi) cells (see above). Once activated, LTo cells produce chemokines (that is, CC-chemokine ligand 19 (CCL19), CCL21, and CXC-chemokine ligand 13 (CXCL13)) and express adhesion molecules (that is, vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1) and E-selectin), which leads to the formation of secondary lymphoid organs (SLO) during embryogenesis and the first weeks after birth and to the formation of tertiary lymphoid structures (TLS) in inflamed adult tissues.

Microsatellite instability

(MSI). A molecular genetic alteration due to DNA mismatch repair (MMR) deficiency, characterized by the presence of deletions and insertions in the repeated sequences of the genome, also termed microsatellites. MSI is observed in numerous tumours such as colorectal, stomach and endometrial cancers.

Plasmablasts

B cells that have received antigenic stimuli and differentiate into antibody-producing cells or plasma cells. As such, they represent immature plasma cells that proliferate rapidly. They still express antibodies on their surface but produce more antibodies than B cells while being still being able to present antigens to T cells.

Plasma cells

Short-lived or long-lived large lymphocytes that are the end-product of the ultimate stage of B cell differentiation. They are also termed plasmacytes. In mammals, they are located mainly, but not exclusively, in the bone marrow after migrating from lymphoid structures where B cells differentiate following antigenic stimulation. Plasma cells produce and secrete very large amounts of antibodies of different classes of immunoglobulins (that is, immunoglobulin M (IgM), IgG, IgA). They also produce interleukins such as interleukin-6 (IL-6) that can act in a paracrine or autocrine manner due to the expression of its receptor on these cells.

Somatic hypermutation

A molecular mechanism involving activation-induced cytidine deaminase (AID) and a low-fidelity DNA polymerase, Polη, that introduces mutations in the variable domains of immunoglobulin genes of B cells present in germinal centres. It leads to the generation of a B cell repertoire that is then affinity-sorted, allowing for the selection of high-affinity antibodies.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Teillaud, JL., Houel, A., Panouillot, M. et al. Tertiary lymphoid structures in anticancer immunity. Nat Rev Cancer 24, 629–646 (2024). https://doi.org/10.1038/s41568-024-00728-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-024-00728-0

  • Springer Nature Limited

Search

Navigation