Skip to main content

Immunology of Solid Tumors Beyond Tumor-Infiltrating Lymphocytes: The Role of Tertiary Lymphoid Structures

  • Chapter
  • First Online:
Biomarkers of the Tumor Microenvironment

Abstract

Immune cells and other constituents of the immune system make up an important part of the tumor microenvironment. Due to increased knowledge on the biology of the immune system in solid tumors and the successes with the treatment of patients with drugs that target its function, interest in immuno-oncology has increased enormously since the first successful trials. The first part of this chapter gives an overview of our current understanding of the role of the immune system in solid tumors, with a focus on the role of tumor-infiltrating lymphocytes (TILs) and their organization in structures called tertiary lymphoid structures (TLS). The increased interest in immuno-oncology has also triggered the search for predictive and prognostic biomarkers. One of the best characterized tissue-based biomarkers of the immune response in solid tumor is the presence of TILs. The second part of the chapter, which focuses on breast cancer, describes currently available data on TILs as a prognostic biomarker, challenges on the assessment of TILs, and TLS and the efforts of the International Immuno-Oncology Biomarker Working Group on standardization of its assessment.

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

Access this chapter

Institutional subscriptions

References

  1. van de Pavert SA, Mebius RE. New insights into the development of lymphoid tissues. Nat Rev Immunol. 2010;10(9):664–74.

    Article  PubMed  Google Scholar 

  2. Drayton DL, Liao S, Mounzer RH, Ruddle NH. Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol. 2006;7(4):344–53.

    Article  CAS  PubMed  Google Scholar 

  3. van de Pavert SA, Mebius RE. Development of secondary lymphoid organs in relation to lymphatic vasculature. Adv Anat Embryol Cell Biol. 2014;214:81–91.

    Article  PubMed  Google Scholar 

  4. Randall TD, Mebius RE. The development and function of mucosal lymphoid tissues: a balancing act with micro-organisms. Mucosal Immunol. 2014;7(3):455–66.

    Article  CAS  PubMed  Google Scholar 

  5. Jones GW, Jones SA. Ectopic lymphoid follicles: inducible centres for generating antigen-specific immune responses within tissues. Immunology. 2016;147(2):141–51.

    Article  CAS  PubMed  Google Scholar 

  6. Stranford S, Ruddle NH. Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organs: parallels with lymph node stroma. Front Immunol. 2012;3:350.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pitzalis C, Jones GW, Bombardieri M, Jones SA. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat Rev Immunol. 2014;14(7):447–62.

    Article  CAS  PubMed  Google Scholar 

  8. Corsiero E, Bombardieri M, Manzo A, Bugatti S, Uguccioni M, Pitzalis C. Role of lymphoid chemokines in the development of functional ectopic lymphoid structures in rheumatic autoimmune diseases. Immunol Lett. 2012;145(1-2):62–7.

    Article  CAS  PubMed  Google Scholar 

  9. Risselada AP, Looije MF, Kruize AA, Bijlsma JW, van Roon JA. The role of ectopic germinal centers in the immunopathology of primary Sjogren’s syndrome: a systematic review. Semin Arthritis Rheum. 2013;42(4):368–76.

    Article  CAS  PubMed  Google Scholar 

  10. Lech M, Anders HJ. The pathogenesis of lupus nephritis. J Am Soc Nephrol. 2013;24(9):1357–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Noort AR, van Zoest KP, van Baarsen LG, Maracle CX, Helder B, Papazian N, et al. Tertiary lymphoid structures in rheumatoid arthritis: NF-kappaB-inducing kinase-positive endothelial cells as central players. Am J Pathol. 2015;185(7):1935–43.

    Article  CAS  PubMed  Google Scholar 

  12. Wang J, Shan Y, Jiang Z, Feng J, Li C, Ma L, et al. High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Exp Immunol. 2013;174(2):212–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kobayashi S, Murata K, Shibuya H, Morita M, Ishikawa M, Furu M, et al. A distinct human CD4+ T cell subset that secretes CXCL13 in rheumatoid synovium. Arthritis Rheum. 2013;65(12):3063–72.

    Article  CAS  PubMed  Google Scholar 

  14. Chang A, Henderson SG, Brandt D, Liu N, Guttikonda R, Hsieh C, et al. In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol. 2011;186(3):1849–60.

    Article  CAS  PubMed  Google Scholar 

  15. Croia C, Astorri E, Murray-Brown W, Willis A, Brokstad KA, Sutcliffe N, et al. Implication of Epstein-Barr virus infection in disease-specific autoreactive B cell activation in ectopic lymphoid structures of Sjogren’s syndrome. Arthritis Rheum. 2014;66(9):2545–57.

    Article  CAS  Google Scholar 

  16. Franciotta D, Salvetti M, Lolli F, Serafini B, Aloisi F. B cells and multiple sclerosis. Lancet Neurol. 2008;7(9):852–8.

    Article  CAS  PubMed  Google Scholar 

  17. Pikor NB, Prat A, Bar-Or A, Gommerman JL. Meningeal tertiary lymphoid tissues and multiple sclerosis: a gathering place for diverse types of immune cells during CNS autoimmunity. Front Immunol. 2015;6:657.

    PubMed  Google Scholar 

  18. Victora GD, Wilson PC. Germinal center selection and the antibody response to influenza. Cell. 2015;163(3):545–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. GeurtsvanKessel CH, Willart MA, Bergen IM, van Rijt LS, Muskens F, Elewaut D, et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med. 2009;206(11):2339–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boyden AW, Legge KL, Waldschmidt TJ. Pulmonary infection with influenza A virus induces site-specific germinal center and T follicular helper cell responses. PLoS One. 2012;7(7):e40733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Moyron-Quiroz JE, Rangel-Moreno J, Hartson L, Kusser K, Tighe MP, Klonowski KD, et al. Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity. 2006;25(4):643–54.

    Article  CAS  PubMed  Google Scholar 

  22. Sansonno D, Tucci FA, Troiani L, Lauletta G, Montrone M, Conteduca V, et al. Increased serum levels of the chemokine CXCL13 and up-regulation of its gene expression are distinctive features of HCV-related cryoglobulinemia and correlate with active cutaneous vasculitis. Blood. 2008;112(5):1620–7.

    Article  CAS  PubMed  Google Scholar 

  23. Winter S, Loddenkemper C, Aebischer A, Rabel K, Hoffmann K, Meyer TF, et al. The chemokine receptor CXCR5 is pivotal for ectopic mucosa-associated lymphoid tissue neogenesis in chronic Helicobacter pylori-induced inflammation. J Mol Med (Berl). 2010;88(11):1169–80.

    Article  CAS  Google Scholar 

  24. Slight SR, Rangel-Moreno J, Gopal R, Lin Y, Fallert Junecko BA, Mehra S, et al. CXCR5(+) T helper cells mediate protective immunity against tuberculosis. J Clin Invest. 2013;123(2):712–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Lucchesi D, Bombardieri M. The role of viruses in autoreactive B cell activation within tertiary lymphoid structures in autoimmune diseases. J Leukoc Biol. 2013;94(6):1191–9.

    Article  PubMed  Google Scholar 

  26. Morissette MC, Jobse BN, Thayaparan D, Nikota JK, Shen P, Labiris NR, et al. Persistence of pulmonary tertiary lymphoid tissues and anti-nuclear antibodies following cessation of cigarette smoke exposure. Respir Res. 2014;15:49.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mittal S, Revell M, Barone F, Hardie DL, Matharu GS, Davenport AJ, et al. Lymphoid aggregates that resemble tertiary lymphoid organs define a specific pathological subset in metal-on-metal hip replacements. PLoS One. 2013;8(5):e63470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mandache E, Penescu M. Renal subcapsular tertiary lymphoid aggregates in chronic kidney diseases. Romanian J Morphol Embryol. 2011;52(4):1219–25.

    CAS  Google Scholar 

  29. Thaunat O. Pathophysiologic significance of B-cell clusters in chronically rejected grafts. Transplantation. 2011;92(2):121–6.

    Article  PubMed  Google Scholar 

  30. Huibers MM, Gareau AJ, Vink A, Kruit R, Feringa H, Beerthuijzen JM, et al. The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy. J Heart Lung Transplant. 2015;34(5):734–45.

    Article  PubMed  Google Scholar 

  31. Sato M, Hirayama S, Matsuda Y, Wagnetz D, Hwang DM, Guan Z, et al. Stromal activation and formation of lymphoid-like stroma in chronic lung allograft dysfunction. Transplantation. 2011;91(12):1398–405.

    Article  CAS  PubMed  Google Scholar 

  32. Orloff SL, Hwee YK, Kreklywich C, Andoh TF, Hart E, Smith PA, et al. Cytomegalovirus latency promotes cardiac lymphoid neogenesis and accelerated allograft rejection in CMV naive recipients. Am J Transplant. 2011;11(1):45–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zarkhin V, Sarwal MM. The coin toss of B cells in rejection and tolerance: danger versus defense. Semin Immunol. 2012;24(2):86–91.

    Article  CAS  PubMed  Google Scholar 

  34. Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 2009;9:3.

    PubMed  PubMed Central  Google Scholar 

  35. Di Caro G, Marchesi F, Laghi L, Grizzi F. Immune cells: plastic players along colorectal cancer progression. J Cell Mol Med. 2013;17(9):1088–95.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Bremnes RM, Busund LT, Kilvaer TL, Andersen S, Richardsen E, Paulsen EE, et al. The role of tumor infiltrating lymphocytes in development, progression and prognosis of non-small cell lung cancer. J Thorac Oncol. 2016;11(6):789–800.

    Article  PubMed  Google Scholar 

  37. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71.

    Article  CAS  PubMed  Google Scholar 

  38. Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol. 2007;8(8):R157.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Alexe G, Dalgin GS, Scanfeld D, Tamayo P, Mesirov JP, DeLisi C, et al. High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates. Cancer Res. 2007;67(22):10669–76.

    Article  CAS  PubMed  Google Scholar 

  40. Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68(13):5405–13.

    Article  CAS  PubMed  Google Scholar 

  41. Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res. 2008;14(16):5158–65.

    Article  CAS  PubMed  Google Scholar 

  42. Teschendorff AE, Gomez S, Arenas A, El-Ashry D, Schmidt M, Gehrmann M, et al. Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules. BMC Cancer. 2010;10:604.

    Article  PubMed  PubMed Central  Google Scholar 

  43. van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530–6.

    Article  Google Scholar 

  44. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999–2009.

    Article  PubMed  Google Scholar 

  45. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A. 2003;100(18):10393–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ignatiadis M, Singhal SK, Desmedt C, Haibe-Kains B, Criscitiello C, Andre F, et al. Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis. J Clin Oncol. 2012;30(16):1996–2004.

    Article  CAS  PubMed  Google Scholar 

  47. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28(1):105–13.

    Article  CAS  PubMed  Google Scholar 

  48. Desmedt C, Di Leo A, de Azambuja E, Larsimont D, Haibe-Kains B, Selleslags J, et al. Multifactorial approach to predicting resistance to anthracyclines. J Clin Oncol. 2011;29(12):1578–86.

    Article  CAS  PubMed  Google Scholar 

  49. Ladoire S, Mignot G, Dabakuyo S, Arnould L, Apetoh L, Rebe C, et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 2011;224(3):389–400.

    Article  CAS  PubMed  Google Scholar 

  50. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949–55.

    Article  PubMed  Google Scholar 

  51. Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, et al. CD4(+) follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013;123(7):2873–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373–80.

    Article  PubMed  Google Scholar 

  53. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, 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. 2009;69(5):2000–9.

    Google Scholar 

  54. Liu S, Foulkes WD, Leung S, Gao D, Lau S, Kos Z, et al. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Res. 2014;16(5):432.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Denkert C, editor. Increased tumor-associated lymphocytes predict benefit from addition of carboplatin to neoadjuvant therapy for trimple-negative and HER2-positive early breast cancer in the GeparSixgto trial (GBG 66). San Antonion Breast Cancer Symposium 2013; San Antonio, TX; 2013.

    Google Scholar 

  56. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.

    Article  CAS  PubMed  Google Scholar 

  57. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32(27):2959–66.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860–7.

    Article  CAS  PubMed  Google Scholar 

  59. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.

    Article  CAS  PubMed  Google Scholar 

  60. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008;26(27):4410–7.

    Article  CAS  PubMed  Google Scholar 

  61. Coppola D, Nebozhyn M, Khalil F, Dai H, Yeatman T, Loboda A, et al. Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. Am J Pathol. 2011;179(1):37–45.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G. Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res. 2011;71(17):5601–5.

    Article  CAS  PubMed  Google Scholar 

  63. Coronella JA, Spier C, Welch M, Trevor KT, Stopeck AT, Villar H, et al. Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J Immunol. 2002;169(4):1829–36.

    Article  CAS  PubMed  Google Scholar 

  64. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 2011;71(17):5678–87.

    Article  CAS  PubMed  Google Scholar 

  65. Ladoire S, Arnould L, Mignot G, Apetoh L, Rebe C, Martin F, et al. T-bet expression in intratumoral lymphoid structures after neoadjuvant trastuzumab plus docetaxel for HER2-overexpressing breast carcinoma predicts survival. Br J Cancer. 2011;105(3):366–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gu-Trantien C, Willard-Gallo K. Tumor-infiltrating follicular helper T cells: the new kids on the block. Oncoimmunology. 2013;2(10):e26066.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Linnebacher M, Maletzki C. Tumor-infiltrating B cells: the ignored players in tumor immunology. Oncoimmunology. 2012;1(7):1186–8.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Cipponi A, Mercier M, Seremet T, Baurain JF, Theate I, van den Oord J, et al. Neogenesis of lymphoid structures and antibody responses occur in human melanoma metastases. Cancer Res. 2012;72(16):3997–4007.

    Article  CAS  PubMed  Google Scholar 

  69. Ladanyi A, Sebestyen T, Mohos A, Liszkay G, Somlai B, Toth E, et al. Ectopic lymphoid structures in primary cutaneous melanoma. Pathol Oncol Res. 2014;20(4):981–5.

    Article  PubMed  Google Scholar 

  70. Di Caro G, Bergomas F, Grizzi F, Doni A, Bianchi P, Malesci A, 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. 2014;20(8):2147–58.

    Article  PubMed  Google Scholar 

  71. Turksma AW, Coupe VM, Shamier MC, Lam KL, de Weger VA, Belien JA, et al. Extent and location of tumor-infiltrating lymphocytes in microsatellite-stable colon cancer predict outcome to adjuvant active specific immunotherapy. Clin Cancer Res. 2016;22(2):346–56.

    Article  CAS  PubMed  Google Scholar 

  72. Germain C, Gnjatic S, Tamzalit F, Knockaert S, Remark R, Goc J, 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. 2014;189(7):832–44.

    Article  CAS  PubMed  Google Scholar 

  73. Zhu W, Germain C, Liu Z, Sebastian Y, Devi P, Knockaert S, 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. 2015;4(12):e1051922.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Lee HJ, Kim JY, Park IA, Song IH, JH Y, Ahn JH, 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. 2015;144(2):278–88.

    Article  CAS  PubMed  Google Scholar 

  75. Lee HJ, Park IA, Song IH, Shin SJ, Kim JY, JH Y, et al. Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer. J Clin Pathol. 2016;69(5):422–30.

    Article  PubMed  Google Scholar 

  76. Kroeger DR, Milne K, Nelson BH. Tumor infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T cell responses, and superior prognosis in ovarian cancer. Clin Cancer Res. 2016;22(12):3005–15.

    Article  CAS  PubMed  Google Scholar 

  77. Giraldo NA, Becht E, Pages F, Skliris G, Verkarre V, Vano Y, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res. 2015;21(13):3031–40.

    Article  CAS  PubMed  Google Scholar 

  78. Wirsing AM, Rikardsen OG, Steigen SE, Uhlin-Hansen L, Hadler-Olsen E. Characterisation and prognostic value of tertiary lymphoid structures in oral squamous cell carcinoma. BMC Clin Pathol. 2014;14:38.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Hiraoka N, Ino Y, Yamazaki-Itoh R, Kanai Y, Kosuge T, Shimada K. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br J Cancer. 2015;112(11):1782–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Halle S, Dujardin HC, Bakocevic N, Fleige H, Danzer H, Willenzon S, et al. Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells. J Exp Med. 2009;206(12):2593–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Maldonado L, Teague JE, Morrow MP, Jotova I, TC W, Wang C, et al. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci Transl Med. 2014;6(221):221ra13.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Sun YY, Peng S, Han L, Qiu J, Song L, Tsai Y, et al. Local HPV recombinant vaccinia boost following priming with an HPV DNA vaccine enhances local HPV-specific CD8+ T-cell-mediated tumor control in the genital tract. Clin Cancer Res. 2016;22(3):657–69.

    Article  CAS  PubMed  Google Scholar 

  83. Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet. 2015;386(10008):2078–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–14.

    Article  CAS  PubMed  Google Scholar 

  85. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61.

    Article  CAS  PubMed  Google Scholar 

  86. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Slovin S. Biomarkers for immunotherapy in genitourinary malignancies. Urol Oncol. 2016;34(4):205–13.

    Article  CAS  PubMed  Google Scholar 

  88. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.

    Article  CAS  PubMed  Google Scholar 

  89. Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst. 2009;101(21):1446–52.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Loi S, Drubay D, Adams S, Francis PA, Joensuu H, Dieci MVV, et al., editors. Pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy. San Antonio Breast Cancer Symposium 2015. San Antonio, TX; 2015.

    Google Scholar 

  91. Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res. 2012;14(2):R48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014;20(10):2773–82.

    Article  CAS  PubMed  Google Scholar 

  93. West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13(6):R126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Perez EA, Ballman KV, Tenner KS, Thompson EA, Badve SS, Bailey H, et al. Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the N9831 adjuvant trial in patients with early-stage HER2-positive breast cancer. JAMA Oncol. 2016;2(1):56–64.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Pruneri G, Vingiani A, Bagnardi V, Rotmensz N, De Rose A, Palazzo A, et al. Clinical validity of tumor-infiltrating lymphocytes analysis in patients with triple-negative breast cancer. Ann Oncol. 2016;27(2):249–56.

    Article  CAS  PubMed  Google Scholar 

  96. Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol. 2015;26(8):1698–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gert G. G. M. Van den Eynden .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Van den Eynden, G.G.G.M., Salgado, R., Willard-Gallo, K. (2017). Immunology of Solid Tumors Beyond Tumor-Infiltrating Lymphocytes: The Role of Tertiary Lymphoid Structures. In: Akslen, L., Watnick, R. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-319-39147-2_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-39147-2_11

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-39145-8

  • Online ISBN: 978-3-319-39147-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics