Cancer and Metastasis Reviews

, Volume 30, Issue 1, pp 13–25 | Cite as

Tumor microenvironment is multifaceted

  • Catherine Sautès-FridmanEmail author
  • Julien Cherfils-Vicini
  • Diane Damotte
  • Sylvain Fisson
  • Wolf Hervé Fridman
  • Isabelle Cremer
  • Marie-Caroline Dieu-Nosjean


Cancer initiation, progression, and invasion occur in a complex and dynamic microenvironment which depends on the hosts and sites where tumors develop. Tumors arising in mucosal tissues may progress in an inflammatory context linked to local viral and/or bacterial infections. At the opposite, tumors developing in immunoprivileged sites are protected from microorganisms and grow in an immunosuppressive environment. In the present review, we summarize and present our recent data on the influence of infectious context and immune cell infiltration organization in human Non-Small Cell Lung Cancers (NSCLC) progression. We show that stimulation of tumor cells by TLR for viral ssRNA, such as TLR7/8, or bacteria, such as TLR4, promotes cell survival and induces chemoresistance. On the opposite, stimulation by TLR3, receptor for double-stranded viral RNA, decreases tumor cell viability and induces chemosensitivity in some lung tumor cell lines. Since fresh lung tumor cells exhibit a gene expression profile characteristic of TLR-stimulated lung tumor cell lines, we suspect that viral and bacterial influence may not only act on the host immune system but also directly on tumor growth and sensitivity to chemotherapy. The stroma of NSCLC contains tertiary lymphoid structures (or Tumor-induced Bronchus-Associated Lymphoid Tissues (Ti-BALT)) with mature DC, follicular DC, and T and B cells. Two subsets of immature DC, Langerhans cells (LC) and interstitial DC (intDC), were detected in the tumor nests and the stroma, respectively. Here, we show that the densities of the three DC subsets, mature DC, LC, and intDC, are highly predictive of disease-specific survival in a series of 74 early-stage NSCLC patients. We hypothesize that the mature DC may derive from local activation and migration of the immature DC—and especially LC which contact the tumor cells—to the tertiary lymphoid structures, after sampling and processing of the tumor antigens. In view of the prominent role of DC in the immune response, we suggest that the microenvironment of early-stage NSCLC may allow the in situ activation of the adaptive response. Finally, we find that the eyes or brain of mice with growing B cell lymphoma are infiltrated with T cells and that the cytokines produced ex vivo by the tumoral tissues have an impaired Th1 cytokine profile. Our work illustrates that the host and external tumor microenvironments are multifaceted and strongly influence tumor progression and anti-tumor immune responses.


Tumor microenvironment Metastasis Immune response Adaptive immunity Lung cancer Dendritic cell Tertiary lymphoid structure Lymphoma Eye Brain TLR 



Bronchus-Associated Lymphoid Tissue


Cerebral spinal fluid


Cytotoxic T lymphocyte


Dendritic cell


Interstitial DC


Langerhans cell


Lymphotoxin αβ

LTi cell

Lymphoid Tissue inducer cell


Non-Hodgkin lymphomas


Non-small cell lung cancer


Plasmacytoid DC


Primary intraocular lymphoma


Primary cerebral lymphoma


Tumor-induced BALT


Tumor-infiltrating lymphocyte


Tertiary Lymphoid Structure


Toll-like receptors



The authors thank the cellular imaging and cytometry plateform (CICC, Centre de Recherche des Cordeliers, Paris F-75006, France). Authors are grateful to Didier Heudes, Nathalie Rabbe, Virginie Poulot, Ludivine Laurans, Pierre Validire, Valérie Touitou, Cécile Daussy, Sabrina Donnou, Claire Galand, and Hélène Fohrer-Ting for their collaboration to these studies and Fathia Mami-Chouaib for the gift of NSCLC tumor specimens and cell lines. We also thank Jacques Cadranel, Martine Antoine, and Claire Danel for their helpful scientific discussions.

Grant support

This work was supported by the Institut National du Cancer (Grants RC013-C06N631-2005 and C06N748-2006), the Institut National de la Santé et de la Recherche Médicale, the University Pierre and Marie Curie, the University Paris-Descartes, and the Association pour la Recherche contre le Cancer (Grant 05/3751, PEMT 00-03 06/ARC-INCA, 06 Equip., 09/183, 09/194), Cancéropole IDF.


  1. 1.
    Balkwill, F. (2009). Tumour necrosis factor and cancer. Nature Reviews Cancer, 9, 361–371.PubMedCrossRefGoogle Scholar
  2. 2.
    Ohshima, H., Tatemichi, M., & Sawa, T. (2003). Chemical basis of inflammation-induced carcinogenesis. Archives of Biochemistry and Biophysics, 417, 3–11.PubMedCrossRefGoogle Scholar
  3. 3.
    Karin, M., & Greten, F. R. (2005). NF-kappaB: linking inflammation and immunity to cancer development and progression. Nature Reviews Immunology, 5, 749–759.PubMedCrossRefGoogle Scholar
  4. 4.
    Lin, W.-W., & Karin, M. (2007). A cytokine-mediated link between innate immunity, inflammation, and cancer. Journal of Clinical Investigation, 117, 1175–1183.PubMedCrossRefGoogle Scholar
  5. 5.
    Balkwill, F., & Mantovani, A. (2001). Inflammation and cancer: back to Virchow? Lancet, 357, 539–545.PubMedCrossRefGoogle Scholar
  6. 6.
    Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420, 860–867.PubMedCrossRefGoogle Scholar
  7. 7.
    Tartour, E., Latour, S., Mathiot, C., Thiounn, N., Mosseri, V., Joyeux, I., et al. (1995). Variable expression of CD3-zeta chain in tumor-infiltrating lymphocytes (TIL) derived from renal-cell carcinoma: relationship with TIL phenotype and function. International Journal of Cancer, 63, 205–212.CrossRefGoogle Scholar
  8. 8.
    Frydecka, I., Kaczmarek, P., Boćko, D., Kosmaczewska, A., Morilla, R., & Catovsky, D. (1999). Expression of signal-transducing zeta chain in peripheral blood T cells and natural killer cells in patients with Hodgkin’s disease in different phases of the disease. Leukaemia & Lymphoma, 35, 545–554.CrossRefGoogle Scholar
  9. 9.
    Bronstein-Sitton, N., Cohen-Daniel, L., Vaknin, I., Ezernitchi, A. V., Leshem, B., Halabi, A., et al. (2003). Sustained exposure to bacterial antigen induces interferon-gamma-dependent T cell receptor zeta down-regulation and impaired T cell function. Nature Immunology, 4, 957–964.PubMedCrossRefGoogle Scholar
  10. 10.
    Cherfils-Vicini, J., Platonova, S., Gillard, M., Laurans, L., Validire, P., Caliandro, R., et al. (2010). Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. The Journal of Clinical Investigation, 120(4), 1285–1297.PubMedCrossRefGoogle Scholar
  11. 11.
    Dunn, G. P., Koebel, C. M., & Schreiber, R. D. (2006). Interferons, immunity and cancer immunoediting. Nature Reviews Immunology, 6, 836–848.PubMedCrossRefGoogle Scholar
  12. 12.
    BURNET, M. (1957). Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. British Medical Journal, 1, 841–847.PubMedCrossRefGoogle Scholar
  13. 13.
    Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pagès, C., et al. (2006). Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science, 313, 1960–1964.PubMedCrossRefGoogle Scholar
  14. 14.
    Pagès, F., Berger, A., Camus, M., Sanchez-Cabo, F., Costes, A., Molidor, R., et al. (2005). Effector memory T cells, early metastasis, and survival in colorectal cancer. The New England Journal of Medicine, 353, 2654–2666.PubMedCrossRefGoogle Scholar
  15. 15.
    Dieu-Nosjean, M.-C., Antoine, M., Danel, C., Heudes, D., Wislez, M., Poulot, V., et al. (2008). Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. Journal of Clinical Oncology, 26, 4410–4417.PubMedCrossRefGoogle Scholar
  16. 16.
    Fridman, W. H., Galon, J., Dieu-Nosjean, M.-C., Cremer, I., Fisson, S., Damotte, D., Pagès, F., Tartour, E., Sautès-Fridman, C. (2010). Immune infiltration in human cancer: prognostic significance and disease control. Current topics in Microbiology and ImmunologyGoogle Scholar
  17. 17.
    Banchereau, J., & Steinman, R. M. (1998). Dendritic cells and the control of immunity. Nature, 392, 245–252.PubMedCrossRefGoogle Scholar
  18. 18.
    Klechevsky, E., Morita, R., Liu, M., Cao, Y., Coquery, S., Thompson-Snipes, L., et al. (2008). Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity, 29, 497–510.PubMedCrossRefGoogle Scholar
  19. 19.
    Ménétrier-Caux, C., Bain, C., Favrot, M. C., Duc, A., & Blay, J. Y. (1999). Renal cell carcinoma induces interleukin 10 and prostaglandin E2 production by monocytes. British Journal of Cancer, 79, 119–130.PubMedCrossRefGoogle Scholar
  20. 20.
    Almand, B., Resser, J. R., Lindman, B., Nadaf, S., Clark, J. I., Kwon, E. D., et al. (2000). Clinical significance of defective dendritic cell differentiation in cancer. Clinical Cancer Research, 6, 1755–1766.PubMedGoogle Scholar
  21. 21.
    Coventry, B. J., Lee, P.-L., Gibbs, D., & Hart, D. N. J. (2002). Dendritic cell density and activation status in human breast cancer—CD1a, CMRF-44, CMRF-56 and CD-83 expression. British Journal of Cancer, 86, 546–551.PubMedCrossRefGoogle Scholar
  22. 22.
    Gabrilovich, D. I., Chen, H. L., Girgis, K. R., Cunningham, H. T., Meny, G. M., Nadaf, S., et al. (1996). Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Natural Medicines, 2, 1096–1103.CrossRefGoogle Scholar
  23. 23.
    Movassagh, M., Spatz, A., Davoust, J., Lebecque, S., Romero, P., Pittet, M., et al. (2004). Selective accumulation of mature DC-Lamp + dendritic cells in tumor sites is associated with efficient T-cell-mediated antitumor response and control of metastatic dissemination in melanoma. Cancer Research, 64, 2192–2198.PubMedCrossRefGoogle Scholar
  24. 24.
    Vermi, W., Bonecchi, R., Facchetti, F., Bianchi, D., Sozzani, S., Festa, S., et al. (2003). Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. The Journal of Pathology, 200, 255–268.PubMedCrossRefGoogle Scholar
  25. 25.
    Bell, D., Chomarat, P., Broyles, D., Netto, G., Harb, G. M., Lebecque, S., et al. (1999). In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. The Journal of Experimental Medicine, 190, 1417–1426.PubMedCrossRefGoogle Scholar
  26. 26.
    Furihata, M., Ono, Y., Ichikawa, K., Tomita, S., Fujimori, T., & Kubota, K. (2005). Prognostic significance of CD83 positive, mature dendritic cells in the gallbladder carcinoma. Oncology Reports, 14, 353–356.PubMedGoogle Scholar
  27. 27.
    Schwaab, T., Weiss, J. E., Schned, A. R., & Barth, R. J., Jr. (2001). Dendritic cell infiltration in colon cancer. Journal of Immunotherapy, 24, 130–137.CrossRefGoogle Scholar
  28. 28.
    Eisenthal, A., Polyvkin, N., Bramante-Schreiber, L., Misonznik, F., Hassner, A., & Lifschitz-Mercer, B. (2001). Expression of dendritic cells in ovarian tumors correlates with clinical outcome in patients with ovarian cancer. Human Pathology, 32, 803–807.PubMedCrossRefGoogle Scholar
  29. 29.
    Reichert, T. E., Scheuer, C., Day, R., Wagner, W., & Whiteside, T. L. (2001). The number of intratumoral dendritic cells and zeta-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer, 91, 2136–2147.PubMedCrossRefGoogle Scholar
  30. 30.
    Treilleux, I., Blay, J.-Y., Bendriss-Vermare, N., Ray-Coquard, I., Bachelot, T., Guastalla, J.-P., et al. (2004). Dendritic cell infiltration and prognosis of early stage breast cancer. Clinical Cancer Research, 10, 7466–7474.PubMedCrossRefGoogle Scholar
  31. 31.
    Vallabhapurapu, S., & Karin, M. (2009). Regulation and function of NF-kappaB transcription factors in the immune system. Annual Review of Immunology, 27, 693–733.PubMedCrossRefGoogle Scholar
  32. 32.
    Li, X., Jiang, S., & Tapping, R. (2010). Toll-like receptor signaling in cell proliferation and survival. Cytokine, 49, 40422.Google Scholar
  33. 33.
    Rakoff-Nahoum, S., & Medzhitov, R. (2007). Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science, 317, 124–127.PubMedCrossRefGoogle Scholar
  34. 34.
    Xiao, H., Gulen, M. F., Qin, J., Yao, J., Bulek, K., Kish, D., et al. (2007). The toll–interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity, 26, 461–475.PubMedCrossRefGoogle Scholar
  35. 35.
    Huang, B., Zhao, J., Unkeless, J. C., Feng, Z. H., & Xiong, H. (2008). TLR signaling by tumor and immune cells: a double-edged sword. Oncogene, 27, 218–224.PubMedCrossRefGoogle Scholar
  36. 36.
    Ikebe, M., Kitaura, Y., Nakamura, M., Tanaka, H., Yamasaki, A., Nagai, S., et al. (2009). Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. Journal of Surgical Oncology, 100(8), 725–731.PubMedCrossRefGoogle Scholar
  37. 37.
    Killeen, S. D., Wang, J. H., Andrews, E. J., & Redmond, H. P. (2006). Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword? British Journal of Cancer, 95, 247–252.PubMedCrossRefGoogle Scholar
  38. 38.
    Kelly, M. G., Alvero, A. B., Chen, R., Silasi, D.-A., Abrahams, V. M., Chan, S., et al. (2006). TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Research, 66, 3859–3868.PubMedCrossRefGoogle Scholar
  39. 39.
    Szajnik, M., Szczepanski, M., Czystowska, M., Elishaev, E., Mandapathil, M., Nowak-Markwitz, E., et al. (2009). TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene, 28, 4353–4363.PubMedCrossRefGoogle Scholar
  40. 40.
    He, W., Liu, Q., Wang, L., Chen, W., Li, N., & Cao, X. (2007). TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Molecular Immunology, 44, 2850–2859.CrossRefGoogle Scholar
  41. 41.
    Huang, B., Zhao, J., Li, H., He, K.-L., Chen, Y., Chen, S.-H., et al. (2005). Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Research, 65, 5009–5014.PubMedCrossRefGoogle Scholar
  42. 42.
    Jahrsdorfer, B., Mühlenhoff, L., Blackwell, S. E., Wagner, M., Poeck, H., Hartmann, E., et al. (2005). B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clinical Cancer Research, 11, 1490–1499.PubMedCrossRefGoogle Scholar
  43. 43.
    Salaun, B., Coste, I., Rissoan, M.-C., Lebecque, S. J., & Renno, T. (2006). TLR3 can directly trigger apoptosis in human cancer cells. Journal of Immunology, 176, 4894–4901.Google Scholar
  44. 44.
    Salaun, B., Lebecque, S., Matikainen, S., Rimoldi, D., & Romero, P. (2007). Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clinical Cancer Research, 13, 4565–4574.PubMedCrossRefGoogle Scholar
  45. 45.
    Salaun, B., Romero, P., & Lebecque, S. (2007). Toll-like receptors’ two-edged sword: when immunity meets apoptosis. European Journal of Immunology, 37, 3311–3318.PubMedCrossRefGoogle Scholar
  46. 46.
    Chen, K., Huang, J., Gong, W., Iribarren, P., Dunlop, N. M., & Wang, J. M. (2007). Toll-like receptors in inflammation, infection and cancer. International Immunopharmacology, 7, 1271–1285.PubMedCrossRefGoogle Scholar
  47. 47.
    Krieg, A. M. (2007). Development of TLR9 agonists for cancer therapy. Journal of Clinical Investigation, 117, 1184–1194.PubMedCrossRefGoogle Scholar
  48. 48.
    Kumar, H., Kawai, T., & Akira, S. (2009). Pathogen recognition in the innate immune response. The Biochemical Journal, 420, 1–16.PubMedCrossRefGoogle Scholar
  49. 49.
    Tsan, M.-F. (2006). Toll-like receptors, inflammation and cancer. Seminars in Cancer Biology, 16, 32–37.PubMedCrossRefGoogle Scholar
  50. 50.
    Kanzler, H., Barrat, F. J., Hessel, E. M., & Coffman, R. L. (2007). Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists. Natural Medicines, 13, 552–559.CrossRefGoogle Scholar
  51. 51.
    Rakoff-Nahoum, S., & Medzhitov, R. (2009). Toll-like receptors and cancer. Nature Reviews Cancer, 9, 57–63.PubMedCrossRefGoogle Scholar
  52. 52.
    Schön, M. P., & Schön, M. (2008). TLR7 and TLR8 as targets in cancer therapy. Oncogene, 27, 190–199.PubMedCrossRefGoogle Scholar
  53. 53.
    Littman, A. J., Jackson, L. A., & Vaughan, T. L. (2005). Chlamydia pneumoniae and lung cancer: epidemiologic evidence. Cancer Epidemiol Biomarkers and Prevention, 14, 773–778.CrossRefGoogle Scholar
  54. 54.
    Littman, A. J., Thornquist, M. D., White, E., Jackson, L. A., Goodman, G. E., & Vaughan, T. L. (2004). Prior lung disease and risk of lung cancer in a large prospective study. Cancer Causes & Control, 15, 819–827.CrossRefGoogle Scholar
  55. 55.
    Littman, A. J., White, E., Jackson, L. A., Thornquist, M. D., Gaydos, C. A., Goodman, G. E., et al. (2004). Chlamydia pneumoniae infection and risk of lung cancer. Cancer Epidemiol Biomarkers and Prevention, 13, 1624–1630.Google Scholar
  56. 56.
    Philip, M., Rowley, D. A., & Schreiber, H. (2004). Inflammation as a tumor promoter in cancer induction. Seminars in Cancer Biology, 14, 433–439.PubMedCrossRefGoogle Scholar
  57. 57.
    Qin, J., Yao, J., Cui, G., Xiao, H., Kim, T. W., Fraczek, J., et al. (2006). TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent. The Journal of Biological Chemistry, 281, 21013–21021.PubMedCrossRefGoogle Scholar
  58. 58.
    Huang, B., Zhao, J., Shen, S., Li, H., He, K.-L., Shen, G.-X., et al. (2007). Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. Cancer Research, 67, 4346–4352.PubMedCrossRefGoogle Scholar
  59. 59.
    Luo, J.-L., Maeda, S., Hsu, L.-C., Yagita, H., & Karin, M. (2004). Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell, 6, 297–305.PubMedCrossRefGoogle Scholar
  60. 60.
    Sfondrini, L., Rossini, A., Besusso, D., Merlo, A., Tagliabue, E., Mènard, S., et al. (2006). Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer. Journal of Immunology, 176, 6624–6630.Google Scholar
  61. 61.
    Earl, T., Nicoud, I., Pierce, J., Wright, J., Majoras, N., Rubin, J., et al. (2009). Silencing of TLR4 Decreases Liver Tumor Burden in a Murine Model of Colorectal Metastasis and Hepatic Steatosis. Annals of Surgical Oncology, 16, 1043–1050.PubMedCrossRefGoogle Scholar
  62. 62.
    Tesniere, A., Schlemmer, F., Boige, V., Kepp, O., Martins, I., Ghiringhelli, F., et al. (2010). Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene, 29, 482–491.PubMedCrossRefGoogle Scholar
  63. 63.
    Chiron, D., Pellat-Deceunynck, C., Amiot, M., Bataille, R., & Jego, G. (2009). TLR3 ligand induces NF-{kappa}B activation and various fates of multiple myeloma cells depending on IFN-{alpha} production. Journal of Immunology, 182, 4471–4478.CrossRefGoogle Scholar
  64. 64.
    Wang, Q., Nagarkar, D., Bowman, E., Schneider, D., Gosangi, B., Lei, J., et al. (2009). Role of double-stranded RNA pattern recognition receptors in rhinovirus-induced airway epithelial cell responses. Journal of Immunology, 183, 6989–6997.CrossRefGoogle Scholar
  65. 65.
    Peng, S., Geng, J., Sun, R., Tian, Z., & Wei, H. (2008). Polyinosinic-polycytidylic acid liposome induces human hepatoma cells apoptosis which correlates to the up-regulation of RIG-I like receptors. Cancer Science, 100, 529–536.PubMedCrossRefGoogle Scholar
  66. 66.
    Nakajima, T., Kodama, T., Tsumuraya, M., Shimosato, Y., & Kameya, T. (1985). S-100 protein-positive Langerhans cells in various human lung cancers, especially in peripheral adenocarcinomas. Virchows Archiv. A, Pathological Anatomy and Histopathology, 407, 177–189.PubMedCrossRefGoogle Scholar
  67. 67.
    Demedts, I. K., Brusselle, G. G., Vermaelen, K. Y., & Pauwels, R. A. (2005). Identification and characterization of human pulmonary dendritic cells. American Journal of Respiratory Cell and Molecular Biology, 32, 177–184.PubMedCrossRefGoogle Scholar
  68. 68.
    Tazi, A., Bouchonnet, F., Grandsaigne, M., Boumsell, L., Hance, A. J., & Soler, P. (1993). Evidence that granulocyte macrophage-colony-stimulating factor regulates the distribution and differentiated state of dendritic cells/Langerhans cells in human lung and lung cancers. The Journal of Clinical Investigation, 91, 566–576.PubMedCrossRefGoogle Scholar
  69. 69.
    Asselin-Paturel, C., Pardoux, C., Gay, F., & Chouaib, S. (1998). Failure of TGF beta1 and IL-12 to regulate human FasL and mTNF alloreactive cytotoxic T-cell pathways. Tissue Antigens, 51, 242–249.PubMedCrossRefGoogle Scholar
  70. 70.
    Arenberg, D. A., Keane, M. P., DiGiovine, B., Kunkel, S. L., Strom, S. R., Burdick, M. D., et al. (2000). Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines. Cancer Immunology, Immunotherapy, 49, 63–70.PubMedCrossRefGoogle Scholar
  71. 71.
    Põld, M., Zhu, L. X., Sharma, S., Burdick, M. D., Lin, Y., Lee, P. P. N., et al. (2004). Cyclooxygenase-2-dependent expression of angiogenic CXC chemokines ENA-78/CXC Ligand (CXCL) 5 and interleukin-8/CXCL8 in human non-small cell lung cancer. Cancer Research, 64, 1853–1860.PubMedCrossRefGoogle Scholar
  72. 72.
    Cao, T., Ueno, H., Glaser, C., Fay, J. W., Palucka, A. K., & Banchereau, J. (2007). Both Langerhans cells and interstitial DC cross-present melanoma antigens and efficiently activate antigen-specific CTL. European Journal of Immunology, 37, 2657–2667.PubMedCrossRefGoogle Scholar
  73. 73.
    Marchal-Sommé, J., Uzunhan, Y., Marchand-Adam, S., Valeyre, D., Soumelis, V., Crestani, B., et al. (2006). Cutting edge: nonproliferating mature immune cells form a novel type of organized lymphoid structure in idiopathic pulmonary fibrosis. Journal of Immunology, 176, 5735–5739.Google Scholar
  74. 74.
    Wakabayashi, O., Yamazaki, K., Oizumi, S., Hommura, F., Kinoshita, I., Ogura, S., et al. (2003). CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Science, 94, 1003–1009.PubMedCrossRefGoogle Scholar
  75. 75.
    Tartour, E., Gey, A., Sastre-Garau, X., Lombard Surin, I., Mosseri, V., & Fridman, W. H. (1998). Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas. Journal of the National Cancer Institute, 90, 287–294.PubMedCrossRefGoogle Scholar
  76. 76.
    Yu, P., Lee, Y., Liu, W., Chin, R. K., Wang, J., Wang, Y., et al. (2004). Priming of naive T cells inside tumors leads to eradication of established tumors. Nature Immunology, 5, 141–149.PubMedCrossRefGoogle Scholar
  77. 77.
    Kirk, C. J., Hartigan-O’Connor, D., Nickoloff, B. J., Chamberlain, J. S., Giedlin, M., Aukerman, L., et al. (2001). T cell-dependent antitumor immunity mediated by secondary lymphoid tissue chemokine: augmentation of dendritic cell-based immunotherapy. Cancer Research, 61, 2062–2070.PubMedGoogle Scholar
  78. 78.
    Moyron-Quiroz, J. E., Rangel-Moreno, J., Kusser, K., Hartson, L., Sprague, F., Goodrich, S., et al. (2004). Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Natural Medicines, 10, 927–934.CrossRefGoogle Scholar
  79. 79.
    Tesar, B. M., Chalasani, G., Smith-Diggs, L., Baddoura, F. K., Lakkis, F. G., & Goldstein, D. R. (2004). Direct antigen presentation by a xenograft induces immunity independently of secondary lymphoid organs. Journal of Immunology, 173, 4377–4386.Google Scholar
  80. 80.
    Moyron-Quiroz, J. E., Rangel-Moreno, J., Hartson, L., Kusser, K., Tighe, M. P., Klonowski, K. D., et al. (2006). Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity, 25, 643–654.PubMedCrossRefGoogle Scholar
  81. 81.
    Drayton, D. L., Liao, S., Mounzer, R. H., & Ruddle, N. H. (2006). Lymphoid organ development: from ontogeny to neogenesis. Nature Immunology, 7, 344–353.PubMedCrossRefGoogle Scholar
  82. 82.
    Rangel-Moreno, J., Carragher, D., & Randall, T. D. (2007). Role of lymphotoxin and homeostatic chemokines in the development and function of local lymphoid tissues in the respiratory tract. Inmunologia (Barcelona, Spain: 1987), 26, 13–28.Google Scholar
  83. 83.
    GeurtsvanKessel, C. H., Willart, M. A. M., Bergen, I. M., van Rijt, L. S., Muskens, F., Elewaut, D., et al. (2009). Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. The Journal of Experimental Medicine, 206, 2339–2349.PubMedCrossRefGoogle Scholar
  84. 84.
    Halle, S., Dujardin, H. C., Bakocevic, N., Fleige, H., Danzer, H., Willenzon, S., et al. (2009). Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells. The Journal of Experimental Medicine, 206, 2593–2601.PubMedCrossRefGoogle Scholar
  85. 85.
    Cassoux, N., Merle-Beral, H., Leblond, V., Bodaghi, B., Miléa, D., Gerber, S., et al. (2000). Ocular and central nervous system lymphoma: clinical features and diagnosis. Ocular Immunology and Inflammation, 8, 243–250.PubMedCrossRefGoogle Scholar
  86. 86.
    Coupland, S. E., & Heimann, H. (2004). Primary intraocular lymphoma. Der Ophthalmologe, 101, 87–98.PubMedCrossRefGoogle Scholar
  87. 87.
    Pantanelli, S. M., Li, Z., Fariss, R., Mahesh, S. P., Liu, B., & Nussenblatt, R. B. (2009). Differentiation of malignant B-lymphoma cells from normal and activated T-cell populations by their intrinsic autofluorescence. Cancer Research, 69, 4911–4917.PubMedCrossRefGoogle Scholar
  88. 88.
    Touitou, V., Daussy, C., Bodaghi, B., Camelo, S., de Kozak, Y., Lehoang, P., et al. (2007). Impaired th1/tc1 cytokine production of tumor-infiltrating lymphocytes in a model of primary intraocular B-cell lymphoma. Investigative Ophthalmology & Visual Science, 48, 3223–3229.CrossRefGoogle Scholar
  89. 89.
    Akpek, E. K., Ahmed, I., Hochberg, F. H., Soheilian, M., Dryja, T. P., Jakobiec, F. A., et al. (1999). Intraocular-central nervous system lymphoma: clinical features, diagnosis, and outcomes. Ophthalmology, 106, 1805–1810.PubMedCrossRefGoogle Scholar
  90. 90.
    Akpek, E. K., Maca, S. M., Christen, W. G., & Foster, C. S. (1999). Elevated vitreous interleukin-10 level is not diagnostic of intraocular-central nervous system lymphoma. Ophthalmology, 106, 2291–2295.PubMedCrossRefGoogle Scholar
  91. 91.
    Char, D. H., Ljung, B. M., Deschênes, J., & Miller, T. R. (1988). Intraocular lymphoma: immunological and cytological analysis. The British Journal of Ophthalmology, 72, 905–911.PubMedCrossRefGoogle Scholar
  92. 92.
    Char, D. H., Ljung, B. M., Miller, T., & Phillips, T. (1988). Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management. Ophthalmology, 95, 625–630.PubMedGoogle Scholar
  93. 93.
    Corriveau, C., Easterbrook, M., & Payne, D. (1986). Lymphoma simulating uveitis (masquerade syndrome). Canadian Journal of Ophthalmology, 21, 144–149.PubMedGoogle Scholar
  94. 94.
    Coupland, S. E., & Damato, B. (2008). Understanding intraocular lymphomas. Clin Experiment Ophthalmol, 36, 564–578.PubMedCrossRefGoogle Scholar
  95. 95.
    Pagès, F., Galon, J., Dieu-Nosjean, M.-C., Tartour, E., Sautès-Fridman, C., & Fridman, W.-H. (2010). Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene, 29, 1093–1102.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Catherine Sautès-Fridman
    • 1
    • 2
    • 3
    Email author
  • Julien Cherfils-Vicini
    • 1
    • 2
    • 3
  • Diane Damotte
    • 1
    • 2
    • 3
    • 4
  • Sylvain Fisson
    • 1
    • 2
    • 3
  • Wolf Hervé Fridman
    • 1
    • 2
    • 3
    • 5
  • Isabelle Cremer
    • 1
    • 2
    • 3
  • Marie-Caroline Dieu-Nosjean
    • 1
    • 2
    • 3
  1. 1.Centre de Recherche des Cordeliers, Team 13Institut National de la Santé et de la Recherche Médicale (INSERM) U872ParisFrance
  2. 2.Université Pierre et Marie Curie-Paris 6UMRS 872, ParisFrance
  3. 3.Université Paris DescartesUMRS 872, ParisFrance
  4. 4.Service d’Anatomo-pathologieHôpital Hôtel Dieu, AP-HPParisFrance
  5. 5.Service d’Immunologie BiologiqueHôpital Européen Georges Pompidou, AP-HPParisFrance

Personalised recommendations