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Tertiary lymphoid structures in the era of cancer immunotherapy

Nature Reviews Cancer volume 19, pages 307–325 (2019)Cite this article

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Abstract

Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours. Key common characteristics between secondary lymphoid organogenesis and TLS neogenesis have been identified. TLSs exist under different maturation states in tumours, culminating in germinal centre formation. The mechanisms that underlie the role of TLSs in the adaptive antitumour immune response are being deciphered. The description of the correlation between TLS presence and clinical benefit in patients with cancer, suggesting that TLSs could be a prognostic and predictive factor, has drawn strong interest into investigating the role of TLSs in tumours. A current major challenge is to exploit TLSs to promote lymphocyte infiltration, activation by tumour antigens and differentiation to increase the antitumour immune response. Several approaches are being developed using chemokines, cytokines, antibodies, antigen-presenting cells or synthetic scaffolds to induce TLS formation. Strategies aiming to induce TLS neogenesis in immune-low tumours and in immune-high tumours, in this case, in combination with therapeutic agents dampening the inflammatory environment and/or with immune checkpoint inhibitors, represent promising avenues for cancer treatment.

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Fig. 1: Tertiary lymphoid structures in different cancer types.
Fig. 2: Pan-cancer gene expression analysis of tertiary lymphoid structure markers in 9,880 tumours.
Fig. 3: The composition and function of tertiary lymphoid structures in cancer.
Fig. 4: Tertiary lymphoid structure manipulation in poor prognostic tumours.

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References

  1. Vogelstein, B. et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319, 525–532 (1988).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Fridman, W. H., Zitvogel, L., Sautès–Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Drayton, D. L., Liao, S., Mounzer, R. H. & Ruddle, N. H. Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7, 344–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Dieu-Nosjean, M.-C. et al. Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol. Rev. 271, 260–275 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Lucchesi, D. & Bombardieri, M. The role of viruses in autoreactive B cell activation within tertiary lymphoid structures in autoimmune diseases. J. Leukoc. Biol. 94, 1191–1199 (2013).

    Article  PubMed  CAS  Google Scholar 

  9. Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Dieu-Nosjean, M.-C., Goc, J., Giraldo, N. A., Sautès-Fridman, C. & Fridman, W. H. Tertiary lymphoid structures in cancer and beyond. Trends Immunol. 35, 571–580 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6, 205–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Thaunat, O. et al. Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc. Natl Acad. Sci. USA 102, 14723–14728 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Thaunat, O. et al. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J. Immunol. 185, 717–728 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10, 927–934 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Ramos-Casals, M., De Vita, S. & Tzioufas, A. G. Hepatitis C virus, Sjögren’s syndrome and B cell lymphoma: linking infection, autoimmunity and cancer. Autoimmun. Rev. 4, 8–15 (2005).

    Article  PubMed  Google Scholar 

  17. Mazzucchelli, L. et al. BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma. J. Clin. Invest. 104, R49–R54 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sautès-Fridman, C. et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front. Immunol. 7, 407 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 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). This study shows that HEVs located around TLSs are gateways for lymphocyte entry into TLSs and have a positive prognostic impact.

    Article  CAS  PubMed  Google Scholar 

  20. 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 describes the favourable prognostic impact of follicular B cells and the production of antitumour antibodies by intratumoural B cells.

    Article  CAS  PubMed  Google Scholar 

  21. 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). This paper describes the favourable impact of tumour-infiltrating plasma cells on the antitumour immune response.

    Article  CAS  PubMed  Google Scholar 

  22. 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). This paper demonstrates the impact of mature DCs located in TLSs on the antitumoural activity of CD8 + T cells: DC-LAMP + DCs confer a prognostic value upon CD8 + T cells in tumours.

    Article  CAS  PubMed  Google Scholar 

  23. Di Caro, G. et al. Occurrence of tertiary lymphoid tissue is associated with T cell infiltration and predicts better prognosis in early-stage colorectal cancers. Clin. Cancer Res. 20, 2147–2158 (2014).

    Article  PubMed  CAS  Google Scholar 

  24. 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 

  25. Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti–PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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). This paper shows that TLS presence is associated with pathological response to neoadjuvant anti-PD1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thommen, D. S. et al. A transcriptionally and functionally distinct PD-1+ CD8 +T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24, 994–1004 (2018). This study demonstrates that PD1 hi CD8 + T cells secreting CXCL13 are predominantly located in TLSs and predict response to anti-PD1 in patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maldonado, L. et al. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci. Transl Med. 6, 221ra13 (2014). This study shows induction of TLSs upon therapeutic vaccination.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Hill, D. G. et al. Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development. Int. J. Cancer 143, 167–178 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Spratt, J. S. & Spjut, H. J. Prevalence and prognosis of individual clinical and pathologic variables associated with colorectal carcinoma. Cancer 20, 1976–1985 (1967).

    Article  PubMed  Google Scholar 

  36. Ladányi, A. et al. Density of DC-LAMP+mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol. Immunother. 56, 1459–1469 (2007).

    Article  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Nielsen, J. S. et al. CD20+tumor-infiltrating lymphocytes have an atypical CD27− memory phenotype and together with CD8+T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 18, 3281–3292 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Gu-Trantien, C. et al. CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer. JCI Insight 2, 91487 (2017).

    Article  PubMed  Google Scholar 

  40. 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 

  41. Streeter, P. R., Rouse, B. T. & Butcher, E. C. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J. Cell Biol. 107, 1853–1862 (1988).

    Article  CAS  PubMed  Google Scholar 

  42. Girard, J.-P. & Springer, T. A. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol. Today 16, 449–457 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. 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  CAS  Google Scholar 

  44. 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 

  45. 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  CAS  Google Scholar 

  46. Gobert, M. et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 69, 2000–2009 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Ruddle, N. H. High endothelial venules and lymphatic vessels in tertiary lymphoid organs: characteristics, functions, and regulation. Front. Immunol. 7, 491 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. 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 

  49. García-Hernández, M. L. et al. A unique cellular and molecular microenvironment is present in tertiary lymphoid organs of patients with spontaneous prostate cancer regression. Front. Immunol. 8, 563 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Carrega, P. et al. NCR(+)ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat. Commun. 6, 8280 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. 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  CAS  Google Scholar 

  52. 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). This paper demonstrates the application of a 12-chemokine gene signature for TLS detection.

    Article  PubMed  PubMed Central  Google Scholar 

  53. 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  CAS  Google Scholar 

  54. Prabhakaran, S. et al. Evaluation of invasive breast cancer samples using a 12-chemokine gene expression score: correlation with clinical outcomes. Breast Cancer Res. 19, 71 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Gu-Trantien, C. et al. CD4+follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Invest. 123, 2873–2892 (2013). This study describes the favourable prognostic impact of PD1 hi CD4 + T FH cells secreting CXCL13 located in TLSs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Becht, E. et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin. Cancer Res. 22, 4057–4066 (2016).

    Article  CAS  PubMed  Google Scholar 

  57. Becht, E. et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 17, 218 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. 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 

  59. Lee, M. et al. Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis. Mod. Pathol. 32, 70–80 (2018). This study demonstrates that the organs to which melanoma metastases seed also influence TLS densities.

    Article  PubMed  CAS  Google Scholar 

  60. Silin¸a, 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). This paper shows that TLSs are impaired by corticosteroids.

    Article  CAS  Google Scholar 

  61. Neesse, A. et al. Stromal biology and therapy in pancreatic cancer. Gut 60, 861–868 (2011).

    Article  PubMed  Google Scholar 

  62. Posch, F. et al. Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. Oncoimmunology 7, e1378844 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  63. 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 

  64. Castino, G. F. et al. Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma. Oncoimmunology 5, e1085147 (2016).

    Article  PubMed  CAS  Google Scholar 

  65. Wirsing, A. M. et al. Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carcinoma. Mod. Pathol. 31, 910–922 (2018).

    Article  CAS  PubMed  Google Scholar 

  66. 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 

  67. Savas, P. et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat. Rev. Clin. Oncol. 13, 228–241 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Schlößer, H. A. et al. B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies. Oncoimmunology 8, e1512458 (2019).

    Article  PubMed  Google Scholar 

  70. 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 

  71. 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 

  72. Petitprez, F. et al. A novel transcriptomic-based immune classification of soft tissue sarcoma (STS) and its association with molecular characteristics, clinical outcome and response to therapy [abstract]. Cancer Res. 78 (Suppl. 13), 4045 (2018).

    Google Scholar 

  73. Wouters, M. C. A. & Nelson, B. H. Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer. Clin. Cancer Res. 24, 6125–6135 (2018).

    Article  PubMed  CAS  Google Scholar 

  74. Gnjatic, S. et al. Survey of naturally occurring CD4+T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc. Natl Acad. Sci. USA 100, 8862–8867 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Prilliman, K. R. et al. Cutting edge: a crucial role for B7-CD28 in transmitting T help from APC to CTL. J. Immunol. 169, 4094–4097 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Schoenberger, S. P., Toes, R. E., van der Voort, E. I., Offringa, R. & Melief, C. J. T cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393, 480–483 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Bennett, S. R. et al. Help for cytotoxic-T cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. 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  CAS  Google Scholar 

  79. Scheper, W. et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat. Med. 25, 89–94 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Simoni, Y. et al. Bystander CD8+T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Becht, E. et al. Immune contexture, immunoscore, and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers. Adv. Immunol. 130, 95–190 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Calderaro, J. et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J. Hepatol. 67, 727–738 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Pikarsky, E. & Heikenwalder, M. Focal and local: ectopic lymphoid structures and aggregates of myeloid and other immune cells in liver. Gastroenterology 151, 780–783 (2016).

    Article  PubMed  Google Scholar 

  85. Sautès-Fridman, C. & Fridman, W. H. TLS in tumors: what lies within. Trends Immunol. 37, 1–2 (2016).

    Article  PubMed  CAS  Google Scholar 

  86. Kuang, D.-M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 51, 154–164 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Chen, M.-M. et al. Polarization of tissue-resident TFH-like cells in human hepatoma bridges innate monocyte inflammation and M2b macrophage polarization. Cancer Discov. 6, 1182–1195 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Xiao, X. et al. PD-1hi identifies a novel regulatory B cell population in human hepatoma that promotes disease progression. Cancer Discov. 6, 546–559 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. 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 (2018). Together with Finkin et al., this paper shows that the location of TLSs is important for their antitumour function. TLSs located in inflamed tumour-adjacent zones have a pro-tumoural role and can serve as a niche for tumour cell progenitors in HCC, favouring late recurrence. Intratumoural TLSs have a favourable prognostic impact on early recurrence in HCC.

    Article  PubMed  Google Scholar 

  90. Martinet, L. et al. High endothelial venules (HEVs) in human melanoma lesions: Major gateways for tumor-infiltrating lymphocytes. Oncoimmunology 1, 829–839 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Koti, M. et al. Tertiary lymphoid structures associate with tumour stage in urothelial bladder cancer. Bladder Cancer 3, 259–267 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Liu, X. et al. Distinct tertiary lymphoid structure associations and their prognostic relevance in HER2 positive and negative breast cancers. Oncologist 22, 1316–1324 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Figenschau, S. L., Fismen, S., Fenton, K. A., Fenton, C. & Mortensen, E. S. Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients. BMC Cancer 15, 101 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Buisseret, L. et al. Tumor-infiltrating lymphocyte composition, organization and PD-1/ PD-L1 expression are linked in breast cancer. Oncoimmunology 6, e1257452 (2017).

    Article  PubMed  CAS  Google Scholar 

  95. Cimino-Mathews, A. et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum. Pathol. 47, 52–63 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Schweiger, T. et al. Tumor-infiltrating lymphocyte subsets and tertiary lymphoid structures in pulmonary metastases from colorectal cancer. Clin. Exp. Metastasis 33, 727–739 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M. & Swartz, M. A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749–752 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Colbeck, E. J. et al. Treg depletion licenses T cell–driven HEV neogenesis and promotes tumor destruction. Cancer Immunol. Res. 5, 1005–1015 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hindley, J. P. et al. T cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T cell depletion. Cancer Res. 72, 5473–5482 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Neyt, K., GeurtsvanKessel, C. H., Deswarte, K., Hammad, H. & Lambrecht, B. N. Early IL-1 signaling promotes iBALT induction after influenza virus infection. Front. Immunol. 7, 312 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Kennedy, C. L. et al. The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17. J. Pathol. 225, 255–264 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. 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 

  103. 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 

  104. Giraldo, N. A. et al. Tumor-infiltrating and peripheral blood T cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin. Cancer Res. 23, 4416–4428 (2017).

    Article  CAS  PubMed  Google Scholar 

  105. Giraldo, N. A., Becht, E., Vano, Y., Sautès-Fridman, C. & Fridman, W. H. The immune response in cancer: from immunology to pathology to immunotherapy. Virchows Arch. 467, 127–135 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Remark, R. et al. Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: influence of tumor origin. Clin. Cancer Res. 19, 4079–4091 (2013). This study shows that the tumour origin dictates the prognostic impact of CD8 + T cells in lung metastases.

    Article  CAS  PubMed  Google Scholar 

  107. Meshcheryakova, A. et al. B cells and ectopic follicular structures: novel players in anti-tumor programming with prognostic power for patients with metastatic colorectal cancer. PLOS ONE 9, e99008 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Finkelman, F. D. et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu. Rev. Immunol. 8, 303–333 (1990).

    Article  CAS  PubMed  Google Scholar 

  109. Fridman, W. H., Pagès, F., Sautès-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Strom, T. et al. Tumour radiosensitivity is associated with immune activation in solid tumours. Eur. J. Cancer 84, 304–314 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sharabi, A. B., Lim, M., DeWeese, T. L. & Drake, C. G. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 16, e498–e509 (2015).

    Article  PubMed  Google Scholar 

  114. Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Denkert, C. et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 19, 40–50 (2018).

    Article  PubMed  Google Scholar 

  116. Song, I. H. et al. Predictive value of tertiary lymphoid structures assessed by high endothelial venule counts in the neoadjuvant setting of triple-negative breast cancer. Cancer Res. Treat. 49, 399–407 (2017).

    Article  CAS  PubMed  Google Scholar 

  117. Stowman, A. M. et al. Lymphoid aggregates in desmoplastic melanoma have features of tertiary lymphoid structures. Melanoma Res. 28, 237 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Eroglu, Z. et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553, 347–350 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Boivin, G. et al. Cellular composition and contribution of tertiary lymphoid structures to tumor immune infiltration and modulation by radiation therapy. Front. Oncol. 8, 256 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 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  CAS  Google Scholar 

  121. Allen, E. et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl Med. 9, eaak9679 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. 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 

  123. 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 paper demonstrates that targeting LIGHT to tumour vessels via a VTP induces formation of intratumoural TLSs and prolongs survival in combination with immune checkpoint inhibitors in mice.

    Article  CAS  PubMed  Google Scholar 

  124. Chen, L. et al. Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells. Cancer Gene Ther. 20, 469–477 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Weinstein, A. M. et al. Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment. OncoImmunology 6, e1322238 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Weinstein, A. M. et al. Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer. Cancer Immunol. Immunother. 68, 109–120 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  127. Yang, S.-C. et al. Intrapulmonary administration of CCL21 gene-modified dendritic cells reduces tumor burden in spontaneous murine bronchoalveolar cell carcinoma. Cancer Res. 66, 3205–3213 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Lee, J. M. et al. Phase I trial of intratumoral injection of CCL21 gene-modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8+T cell infiltration. Clin. Cancer Res. 23, 4556–4568 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhu, G. et al. Induction of tertiary lymphoid structures with antitumor function by a lymph node-derived stromal cell line. Front. Immunol. 9, 1609 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Yagawa, Y. et al. Systematic screening of chemokines to identify candidates to model and create ectopic lymph node structures for cancer immunotherapy. Sci. Rep. 7, 15996 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Zhu, G. et al. Tumor-associated tertiary lymphoid structures: gene-expression profiling and their bioengineering. Front. Immunol. 8, 767 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Weiden, J., Tel, J. & Figdor, C. G. Synthetic immune niches for cancer immunotherapy. Nat. Rev. Immunol. 18, 212–219 (2017).

    Article  PubMed  CAS  Google Scholar 

  133. Jones, G. W., Hill, D. G. & Jones, S. A. Understanding immune cells in tertiary lymphoid organ development: it is all starting to come together. Front. Immunol. 7, 401 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Meier, D. et al. Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity 26, 643–654 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Deteix, C. et al. Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection. J. Immunol. 184, 5344–5351 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Peters, A. et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986–996 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J. Exp. Med. 208, 125–134 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Guedj, K. et al. M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis. Cardiovasc. Res. 101, 434–443 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. Colbeck, E. J., Ager, A., Gallimore, A. & Jones, G. W. Tertiary lymphoid structures in cancer: drivers of antitumor immunity, immunosuppression, or bystander sentinels in disease? Front. Immunol. 8, 1830 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Furtado, G. C. et al. Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc. Natl Acad. Sci. USA 104, 5026–5031 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Luther, S. A. et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J. Immunol. 169, 424–433 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. 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 

  143. Denton, A. E. et al. Type I interferon induces CXCL13 to support ectopic germinal center formation. J. Exp. Med. 216, 621–637 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank members of the Cancer and Immune Escape Team UMR_S1136 Cordeliers Research Centre for fruitful discussions and performing experiments, and L. Lacroix and A. Bougouin for help in preparing figure 1. This work was supported by Institut National Français de Recherche Médicale (INSERM), the University Paris Descartes, Sorbonne University, CARPEM T8, the Labex Immuno-Oncology Excellence Program, Institut du Cancer (INCa), HTE Plan Cancer (C1608DS to C.S.F.), PRTK G26 NIVOREN, Foncer contre le cancer, Bionik contracts and the Cartes d’Identité des Tumeurs (CIT) Program from the Ligue Nationale Contre le Cancer. F.P. was supported by a CARPEM doctorate fellowship, and J.C. was supported by an Association pour la Recherche sur le Cancer (ARC) postdoctoral fellowship.

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

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Authors and Affiliations

  1. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université de Paris, Equipe Inflammation, complément et cancer, F-75006, Paris, France

    Catherine Sautès-Fridman, Florent Petitprez, Julien Calderaro & Wolf Herman Fridman

  2. Programme Cartes d’Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France

    Florent Petitprez

  3. Département de Pathologie, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France; Université Paris-Est, Créteil, France

    Julien Calderaro

  4. INSERM U955, Equipe 18, Institut Mondor de Recherche Biomédicale, Créteil, France

    Julien Calderaro

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  1. Catherine Sautès-Fridman
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  2. Florent Petitprez
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  3. Julien Calderaro
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  4. Wolf Herman Fridman
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All authors reviewed and edited the manuscript before submission.

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Correspondence to Catherine Sautès-Fridman.

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Competing interests

C.S.-F. and W.H.F. are on the list of co-inventors on a patent application for the prognostic impact of tertiary lymphoid structures in patients with lung cancer (PCT-EP2016/070158). F.P. and J.C. declare no competing interests.

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Glossary

CD8+ T effector memory cells

A subset of CD8+ T cells with cytotoxic or interferon-γ (IFNγ)-producing functions that provide a long-lasting immunity against previously encountered antigens.

Secondary lymphoid organs

(SLOs). Organs such as the spleen, tonsils or lymph nodes that support antigen presentation to lymphoid cells to initiate and regulate the adaptive immune response.

Germinal centre

A specialized compartment within lymphoid structures that promotes B cell proliferation, differentiation, affinity maturation through somatic hypermutation and class switch recombination.

Somatic hypermutation

A process occurring during the maturation of B cells in germinal centres. Mutations occur in the variable regions of immunoglobulin heavy and light chains, enhancing affinity of the antibody for the antigen.

Class switch recombination

Otherwise known as isotype switching; a mechanism that changes the isotype of immunoglobulin produced by B cells. The constant region of the heavy chain is modified, allowing different effector functions for antibodies, such as complement activation (immunoglobulin M (IgM) and IgG) and Fcγ receptor-dependent activation (IgG), to adapt the humoral response to the antigen stimulus.

Follicular dendritic cells

(FDCs). Reticular cells found in the B cell area of lymphoid follicles. FDCs participate in the organization of the lymphoid structures and express Fcγ receptor and complement receptors. Binding of immunoglobulin G (IgG) antigen–antibody complexes on FDCs enables antigen presentation to B cells and selection of B cells expressing high-affinity antibodies.

Tingible-body macrophages

A type of macrophage found in germinal centres; they are able to phagocytose apoptotic lymphoid cells. Their cytoplasm contains condensed chromatin fragments.

Lymphoid tissue inducer cell

(LTi cell). A lymphoid cell that expresses and produces lymphotoxin-α and induces the formation of lymphoid tissue.

Adrenal glands

Endocrine glands producing hormones that participate in the regulation of the immune system, metabolism and stress. These glands secrete notably cortisol, aldosterone and androgenic steroids.

Breslow thickness

A measure in millimetres of the distance between the upper layer of epidermis and the deepest point of a tumour. This staging system is used as a prognostic factor for melanoma.

Clark level of invasion

A staging method used conjointly with the Breslow thickness to describe the depth of melanoma tumour invasion into the skin.

Evanescent prostate cancer

Prostate cancer with spontaneous regression.

Fuhrman grades

Nuclear grades taking into account size and nuclear outline as well as nucleoli. These correlate with differentiation of tumour cells.

Antibody-dependent cellular cytotoxicity

(ADCC). A process in which target cells are identified by antibodies, which are then recognized by the Fc receptor of natural killer cells and eliminated by cytotoxic molecule release.

Immunological ignorance

A phenomenon associated with immune cold tumour phenotypes in which tumour antigens are not immunogenic or are not presented to lymphocytes to raise an immune response.

Mesothelin

A protein that is physiologically present in mesothelial cells. This protein is immunogenic and overexpressed in several human cancers including pancreatic and lung adenocarcinoma and ovarian cancer and can be used as a tumour marker.

Fibroblastic reticular cells

(FRCs). Specialized stromal cells localized in the T cell zone of the lymph nodes and of tertiary lymphoid structures. FRCs interact with the microenvironment to regulate T cells.

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Sautès-Fridman, C., Petitprez, F., Calderaro, J. et al. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 19, 307–325 (2019). https://doi.org/10.1038/s41568-019-0144-6

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