Breast Cancer Research and Treatment

, Volume 59, Issue 2, pp 141–152 | Cite as

Infiltrating dendritic/Langerhans cells in primary breast cancer

  • Tohru Tsuge
  • Mitsunori Yamakawa
  • Masaru Tsukamoto


It is fully anticipated that dendritic cells (DCs) will become a mainstay for inclusion in biological therapies for patients with cancer including breast cancer. To elucidate the cellular composition of DCs infiltrating human breast cancers, we investigated the correlations between the density of infiltrating DCs and some clinicopathological factors of breast cancer patients, examined cytokine expression on cancer cells and finally, assessed the numbers of CD45RO+ tumor infiltrating lymphocytes (TIL). Tissues adjacent to cancer nests contained significantly more S-100 protein+ and S-100 protein+ CD1a DCs, but less CD1a+ DCs, than the nests. In invasive ductal carcinomas infiltration by S-100 protein+ DCs within and adjacent to nests, CDla+ DCs within nests and S-100 protein+ CD1a DCs adjacent to nests was denser than that in non-invasive carcinomas. With respect to the histological subtypes, there were fewer DCs in scirrhous carcinomas. Patients with stage IV disease had significantly fewer DCs of primary lesions than at other clinical stages. There were good correlations between infiltration by S-100 protein+ DCs and expression of the cytokines GM-CSF, IL-1α and TNF-α on cancer cells and between GM-CSF expression and S-100 protein+ CD1a DCs. There was a close correlation between CD45RO+ TIL and S-100 protein+ DC densities both within and adjacent to the cancer nests and the S-100 protein+ CD1a DC density adjacent to the cancer nests. Despite extensive immunoelectron microscopic observation, CD1a+ DCs within cancer nests contained only few Birbeck's granule-like structure. These data indicate that cancer nests are infiltrated predominantly by CD1a+ DCs, whereas S-100 protein+ CD1a DCs predominate in surrounding tissues, and a infiltration by DCs may require cytokine expression on cancer cells and simultaneous lymphocyte infiltration. The findings of this clinicopathological study indicate the importance of evaluating simultaneously the types and localizations of infiltrating DCs in cancer tissues.

dendritic cells granulocyte macrophage colony stimulating factor interleukin-1α, tumor necrosis factor-α tumor infiltrating lymphocyte 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Tsujitani S, Kakeji Y, Maehara Y, Sugimachi K, Kaibara N: Dendritic cells prevent lymph node metastasis in patients with gastric cancer. in vivo 7: 233–238, 1993Google Scholar
  2. 2.
    Grabbe S, Bruvers S, Gallo LR, Knisely L, Nazareno R, Granstein DR: Tumor antigen presentation by murine epidermal cells. J Immunol 146: 3656–3661, 1991Google Scholar
  3. 3.
    Celluzzi MC, Mayordomo IJ, Storkus JW, Lotze TM, Falo DL: Peptide pulsed dendritic cells induce antigen-specific, CTLmediated protective tumor immunity. J Exp Med 183: 283–287, 1996Google Scholar
  4. 4.
    Condon C, Watkins SC, Celluzzi CM, Thompson K, Falo LD: DNA-based immunization by in vivo transfection of dendritic cells. Nature Med 2: 1122–1128, 1996Google Scholar
  5. 5.
    Hsu JF, Benike C, Fagnoni F, Liles MT, Czerwinski D, Taidi B, Engleman EG, Levy R: Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nature Med 2: 52–58, 1996Google Scholar
  6. 6.
    Mayordomo IJ, Zorina T, Storkus JW, Zitvogel L, Celluzzi C, Falo DL, Melief CJ, Ildstad ST, Kast WM, Deleo AB: Bone marrow-derived dendritic cells pulsed with synthetic tumor peptides elicit protective and therapeutic antitumor immunity. Nature Med 1: 1297–1302, 1995Google Scholar
  7. 7.
    Shamoto M, Osada A, Shinzato M, Kaneko C, Yoshida A: Do epidermal Langerhans cells, migrating from skin lesions, induce the paracortical hyperplasia of dermatopathic lymphadenopathyα Pathol Int 46: 348–354, 1996Google Scholar
  8. 8.
    Cumberbatch M, Gould SJ, Peters SW, Kimber I: MHC class II expression by Langerhans cells and lymph node dendritic cells: Possible evidence for maturation of langerhans cells following contact sensitization. Immunology 74: 414–419, 1991Google Scholar
  9. 9.
    Imai Y, Yamakawa M: Dendritic cells in esophageal cancer and lymph node tissues. in vivo 7: 239–248, 1993Google Scholar
  10. 10.
    Yamakawa M, Yamada K, Orui H, Tsuge T, Ogata T, Dobashi M, Imai Y: Immunohistochemical analysis of dendritic/ Langerhans cells in thyroid carcinoma. Anal Cell Pathol 8: 331–343, 1995Google Scholar
  11. 11.
    Caux C, Dezutter-Dambuyant C, Schmit D, Banchereau J: GM-CSF and TNF-α cooperate in the generation of dendritic langerhans cells. Nature 360: 258–261, 1992Google Scholar
  12. 12.
    Caux C, Massacrier C, Dezutter-Dambuyant C, Vanbervlient B, Jacquet C, Schumitt D, Banchereau J: Human dendritic Langerhans cells generated in vitro from CD34+ prime naive CD4+ T cells and process soluble antigen. J Immunol 155: 5427–5435, 1995Google Scholar
  13. 13.
    Reid CDL, Stackpoole A, Meager A, Tikerpae J: Interactions of tumor necrosis factor with granulocyte macrophage colony stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow. J Immunol 149: 2681–2688, 1992Google Scholar
  14. 14.
    Koide S, Inaba K, Steinman RM: Interleukin-1 enhances Tdependent immune responses by amplifying the function of dendritic cells. J Exp Med 165: 515–530, 1987Google Scholar
  15. 15.
    Kimber I, Cumberbatch M: Stimulation of Langerhans cell migration by tumor necrosis factor α (TNF-α). J Invest Dermatol 99: 48–50, 1992Google Scholar
  16. 16.
    Cumberbatch M, Fielding I, Kimber I: Modulation of epidermal Langerhans cell frequency by tumor necrosis factor-α. Immunology 81: 395–401, 1994Google Scholar
  17. 17.
    Colasante A, Castrilli G, Aiello BF, Brunetti M, Musiani P: Role of cytokines in distribution and differentiation of dendritic cell/Langerhans cell lineage in human primary carcinoma of the lung. Hum Pathol 26: 866–872, 1995Google Scholar
  18. 18.
    Tazi A, Bouchonnet F, Grandsaigne M, Boumsell L, Hance AJ, Soler P: Evidence that granulocyte macrophage-colony stimulating factor regulates the distribution and differentiated state of dendritic cells/Langerhans cells in human lung and lung cancer. J Clin Invest 91: 566–576, 1993Google Scholar
  19. 19.
    Papadimitriou CS, Datersis G, Costopopulos JS, Bai MK, loachim Velogianni E, Katsouyannopoulos V: Langerhans cells and lymphocyte subsets in human gastrointestinal carcinomas: An immunohistochemical study on frozen sections. Path Res Pract 188: 989–994, 1992Google Scholar
  20. 20.
    General Rules for Clinical and Pathological Recording of Breast Cancer (12th edition), The Japanese Breast Cancer Society, July, 1996Google Scholar
  21. 21.
    Hsu SM, Raine L, Fauger H: Use of avidin- biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PA) procedure. J Histochem Cytochem 29: 577–580, 1981Google Scholar
  22. 22.
    Curren RC, Gregory J: Demonstration of immunoglobulin in cryostat and paraffin sections of human tonsil by immunofluoresence and immunoperoxidase techniques. Effects of processing on immunohistochemical performance of tissue and on the use of proteolytic enzymes to unmask antigens in section. J Clin Pathol 31: 974–983, 1978Google Scholar
  23. 23.
    Hume WJ, Keat S: Immunological optimization of detection of bromodeoxyuridine-labeled cells in decalcified tissue. J Histochem Cytochem 38: 509–513, 1990Google Scholar
  24. 24.
    Shin RW, Iwaki T, Kitamoto T: Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues. Lab Invest 64: 693–702, 1991Google Scholar
  25. 25.
    Egan JM, Newman J, Crocker J, Collard M: Immunohistochemical localization of S-100 protein in benign and malignant condition of breast. Arch Pathol Lab Med 111: 28–31, 1987Google Scholar
  26. 26.
    King RJ, Coffer AI, Gilbert J, Lewis K, Nash R, Millis R, Raju S, Taylor RW: Histochemical studies with monoclonal antibody raised against a partially purified soluble estradiol receptor preparation from human myometrium. Cancer Res 45: 5728–5733, 1985Google Scholar
  27. 27.
    Maeda K, Burton GF, Padgett DA, Conrad DH, Huff TF, Masuda A, Szakal AK, Tew JG: Murine follicular dendritic cells and low affinity Fc receptors for IgE (Fcɛ II). J Immunol 148: 2340–2347, 1992Google Scholar
  28. 28.
    Inaba K, Inaba M, Aya H: Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte-macrophage colony stimulating factor. J Exp Med 176: 1693–1703, 1992Google Scholar
  29. 29.
    Girolomoni G, Simon JC, Bergstresser PR, Cruz PO: Freshly isolated spleen dendritic cells and epidermal Langerhans cells undergo similar phenotypic and functional changes during short term culture. J Immunol 145: 2820–2826, 1990Google Scholar
  30. 30.
    Kitajima T, Caceres-Dittmar G, Tapia F-J, Jester J, Bergstresser PR, Takashima A: T cell-mediated terminal maturation of dendritic cells. Loss of adhesive and phagocytic capacities. J Immunol 157: 2340–2347, 1996Google Scholar
  31. 31.
    Imai Y, Yamakawa M, Kasajima T: The lymphocyte-dendritic cell system. Histol Histopathol 13: 469–510, 1998Google Scholar
  32. 32.
    Inaba K, Inaba M, Naito M, Steinman RM: Dendritic cell progenitors phagocytose particles, including Bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J Exp Med 178: 479–488, 1993Google Scholar
  33. 33.
    Sousa CR, Stahl PD, Austyn JM: Phagocytosis of antigens by Langerhans cells in vitro. J Exp Med 178: 509–519, 1993Google Scholar
  34. 34.
    Coates JP, Rowland S, Hill S, Iqball S, Berford PA, Kimber I, Knight SC: Comparison between the phenotype and function of maturating dendritic cells from spleen and lymph nodes. Immunology 89: 457–462, 1996Google Scholar
  35. 35.
    Garrigan K, Moroni-Rawson P, McMurray C, Hermans I, Abernethy N, Watson J, Ronchese F: Functional comparison of splenic dendritic cells and dendritic cells cultured in vitro from bone marrow precursors. Blood 88: 3508–3512, 1996Google Scholar
  36. 36.
    Yamakawa M, Kato H, Takagi S, Karube Y, Seki K, Imai Y: Dendritic cells in various human thyroid diseases. In Vivo 7: 249–256, 1993Google Scholar
  37. 37.
    Tas MP, Simons PJ, Balm FJ, Drexhage HA: Depressed monocyte polarization and clustering of dendritic cells in patients with head and neck cancer: in vitro restoration of this immunosuppression by thymic hormones. Cancer Immunol Immunother 36: 108–114, 1993Google Scholar
  38. 38.
    Kerrebijn JD, Balm AJM, Knegt PP, Meeuwis CA, Drexhage HA: Macrophage and dendritic cell infiltration in head and neck squamous-cell carcinoma; an immunohistochemical study. Cancer Immunol Immunother 38: 31–37, 1994Google Scholar
  39. 39.
    Ishigami S, Aikou T, Natsugoe S, Hokita S, Iwashige H, Tokushige M, Sonoda S: Prognostic value of HLA-DR expression and dendritic cell infiltration in gastric cancer. Oncology 55: 65–69, 1998Google Scholar
  40. 40.
    Cohen PJ, Cohen PA, Rosenberg SA, Katz SI, Mule JJ: Murine epidermal Langerhans cells and splenic dendritic cells present tumor associated antigens to primed T cells. Eur J Immunol 24: 315–319, 1994Google Scholar
  41. 41.
    Nakano T, Oka K, Takahashi T, Morita S, Arai T: Role of Langerhans cells and T-lymphocytes infiltrating cancer tissue in patients treated by radiation therapy for cervical cancer. Cancer 70:2839-2844, 1992Google Scholar
  42. 42.
    Goldman S, Baker E, Weyant RJ, Clarke MR, Myers JN, Lotze MT: Peritumoral CD1a-positive dendritic cells are associated with improved survival in patients with tongue carcinoma. Arch Otolaryngol Head Neck Surg 124: 641–646, 1998Google Scholar
  43. 43.
    Liu C-L, Suri RM, Rahdon RA, Austyn JM, Roake JA: Dendritic cell chemotaxis and transendothelial migration are induced by distinct chemokines and regulated on maturation. Eur J Immunol 28: 4114–4122, 1998Google Scholar
  44. 44.
    Mommaas M, Mulder A, Vermeer BJ, Koning F: Functional human epidermal Langerhans cells that lack Birbeck granules. J Invest Dermatol 103: 807–810, 1994Google Scholar
  45. 45.
    Nakano T, Oka K, Hanba K, Morita S: Intratumoral administration of Sizofiran activates Langerhans cell and T-cell infiltration in cervical cancer. Clin Immunol Immunopathol 79: 79–86, 1996Google Scholar
  46. 46.
    Hanau D, Fabre M, Schmitt DA, Garaud J, Pauly G, Tongio M, Mayer S, Cazanave J: Human epidermal Langerhans cells cointernalize by receptor mediated endocytosis ‘nonclassical’ major histocompatibility complex class I molecules (T6 antigens) and class II molecules (HLA-DR antigens). Proc Natl Acad Sci USA 84: 2901–2905, 1987Google Scholar
  47. 47.
    Dummer W, Becker JC, Schwaaf A, Leverkus M, Moll T, Brocker EB: Elevated serum levels of interleukin-10 in patients with metastatic malignant melanoma. Melanoma Res 5: 67–68, 1995Google Scholar
  48. 48.
    Gabrilovich DI, Chen HI, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP: Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Med 2: 1096–1103, 1996Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Tohru Tsuge
    • 1
    • 2
  • Mitsunori Yamakawa
    • 3
  • Masaru Tsukamoto
    • 2
  1. 1.Second Department of SurgeryYamagata University School of MedicineYamagataJapan
  2. 2.First Department of SurgeryYamagata University School of MedicineYamagataJapan
  3. 3.Yamagata University School of MedicineYamagataJapan

Personalised recommendations