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Metastasis to sentinel lymph nodes in breast cancer is associated with maturation arrest of dendritic cells and poor co-localization of dendritic cells and CD8+ T cells

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Abstract

The regional immune systems of patients with breast cancer are immunosuppressed. Dendritic cells are professional antigen-presenting cells and present cancer-associated antigens to the adaptive immune system in sentinel lymph nodes. Dendritic cells may promote, or inhibit, an adaptive immune response to specific antigens. Our aim was to assess whether dendritic cells were associated with nodal metastasis in patients with breast cancer. Sentinel lymph nodes of 47 patients with breast cancer with varying degrees of nodal disease and ten controls were evaluated using immunohistochemistry for the accumulation of dendritic cells in general (CD1a+), mature dendritic cells (CD208+), and plasmacytoid dendritic cells (CD123+). Cytotoxic T cell and regulatory T cell accumulation were also evaluated. Sentinel lymph nodes with macrometastases demonstrated fewer mature dendritic cells than sentinel lymph nodes without metastasis (p = 0.028), but not controls. There were fewer mature dendritic cells to cytotoxic T cells in sentinel lymph nodes with metastasis than those without (p = 0.033). Also, there were more regulatory T cells to mature dendritic cells in sentinel lymph nodes with metastasis than those without (p = 0.02). In conclusion, our study suggests that sentinel lymph nodes with metastasis have arrest of maturation of dendritic cells, fewer mature dendritic cell interactions with cytotoxic T cells, and more regulatory T cells than sentinel lymph nodes without metastasis in patients with breast cancer. These findings extend our understanding of regional immunosuppression and suggest that most regional immunosuppressive changes are associated with nodal metastasis in breast cancer.

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References

  1. Mansour EG, Ravdin PM, Dressler L (1994) Prognostic factors in early breast carcinoma. Cancer 74(1 Suppl):381–400

    Article  PubMed  CAS  Google Scholar 

  2. Nemoto T, Vana J, Bedwani RN, Baker HW, McGregor FH, Murphy GP (1980) Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 45(12):2917–2924

    Article  PubMed  CAS  Google Scholar 

  3. Rosen PP, Groshen S, Saigo PE, Kinne DW, Hellman S (1989) Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years. J Clin Oncol 7(9):1239–1251

    PubMed  CAS  Google Scholar 

  4. Leidenius MH, Krogerus LA, Toivonen TS, von Smitten KA (2005) Sentinel node biopsy is not sensible in breast cancer patients with large primary tumours. Eur J Surg Oncol 31(4):364–368

    Article  PubMed  CAS  Google Scholar 

  5. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH (2000) Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 192(9):1213–1222

    Article  PubMed  CAS  Google Scholar 

  6. Mahnke K, Schmitt E, Bonifaz L, Enk AH, Jonuleit H (2002) Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunol Cell Biol 80(5):477–483. doi:10.1046/j.1440-1711.2002.01115.x

    Article  PubMed  Google Scholar 

  7. Bembenek A, Li J, Loddenkemper C, Kemmner W, Stein H, Wernecke KD, Schlag PM (2008) Presence of mature DC-Lamp+ dendritic cells in sentinel and non-sentinel lymph nodes of breast cancer patients. Eur J Surg Oncol 34(5):514–518

    Article  PubMed  CAS  Google Scholar 

  8. Huang RR, Wen DR, Guo J, Giuliano AE, Nguyen M, Offodile R, Stern S, Turner R, Cochran AJ (2000) Selective modulation of paracortical dendritic cells and T-lymphocytes in breast cancer sentinel lymph nodes. Breast J 6(4):225–232

    Article  PubMed  Google Scholar 

  9. Poindexter NJ, Sahin A, Hunt KK, Grimm EA (2004) Analysis of dendritic cells in tumor-free and tumor-containing sentinel lymph nodes from patients with breast cancer. Breast Cancer Res 6(4):R408–R415

    Article  PubMed  CAS  Google Scholar 

  10. Treilleux I, Blay JY, Bendriss-Vermare N, Ray-Coquard I, Bachelot T, Guastalla JP, Bremond A, Goddard S, Pin JJ, Barthelemy-Dubois C, Lebecque S (2004) Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res 10(22):7466–7474

    Article  PubMed  CAS  Google Scholar 

  11. Lande R, Gilliet M (2010) Plasmacytoid dendritic cells: key players in the initiation and regulation of immune responses. Ann N Y Acad Sci 1183:89–103. doi:10.1111/j.1749-6632.2009.05152.x

    Article  PubMed  CAS  Google Scholar 

  12. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189(9):1363–1372

    Article  PubMed  CAS  Google Scholar 

  13. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281(5380):1191–1193

    Article  PubMed  CAS  Google Scholar 

  14. Mansfield AS, Heikkila PS, Vaara AT, von Smitten KA, Vakkila JM, Leidenius MH (2009) Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer. BMC Cancer 9:231

    Article  PubMed  Google Scholar 

  15. Matsuura K, Yamaguchi Y, Osaki A, Ohara M, Okita R, Emi A, Murakami S, Arihiro K (2009) FOXP3 expression of micrometastasis-positive sentinel nodes in breast cancer patients. Oncol Rep 22(5):1181–1187

    Article  PubMed  CAS  Google Scholar 

  16. Matsuura K, Yamaguchi Y, Ueno H, Osaki A, Arihiro K, Toge T (2006) Maturation of dendritic cells and T-cell responses in sentinel lymph nodes from patients with breast carcinoma. Cancer 106(6):1227–1236

    Article  PubMed  CAS  Google Scholar 

  17. Kohrt HE, Nouri N, Nowels K, Johnson D, Holmes S, Lee PP (2005) Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer. PLoS Med 2(9):e284

    Article  PubMed  Google Scholar 

  18. Caux C, Massacrier C, Vanbervliet B, Dubois B, de Saint-Vis B, Dezutter-Dambuyant C, Jacquet C, Schmitt D, Banchereau J (1997) CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha. Adv Exp Med Biol 417:21–25

    PubMed  CAS  Google Scholar 

  19. Barral DC, Brenner MB (2007) CD1 antigen presentation: how it works. Nat Rev Immunol 7(12):929–941. doi:10.1038/nri2191

    Article  PubMed  CAS  Google Scholar 

  20. de Saint-Vis B, Vincent J, Vandenabeele S, Vanbervliet B, Pin JJ, Ait-Yahia S, Patel S, Mattei MG, Banchereau J, Zurawski S, Davoust J, Caux C, Lebecque S (1998) A novel lysosome-associated membrane glycoprotein, DC-LAMP, induced upon DC maturation, is transiently expressed in MHC class II compartment. Immunity 9(3):325–336

    Article  PubMed  Google Scholar 

  21. Sobin LHWC (ed) (2002) TNM classification of malignant tumors, 6th edn. Wiley, New York

    Google Scholar 

  22. Leidenius MH, Krogerus LA, Toivonen TS, Von Smitten KJ (2003) The feasibility of intraoperative diagnosis of sentinel lymph node metastases in breast cancer. J Surg Oncol 84(2):68–73

    Article  PubMed  Google Scholar 

  23. Leikola JP, Toivonen TS, Krogerus LA, von Smitten KA, Leidenius MH (2005) Rapid immunohistochemistry enhances the intraoperative diagnosis of sentinel lymph node metastases in invasive lobular breast carcinoma. Cancer 104(1):14–19

    Article  PubMed  Google Scholar 

  24. Angel CE, Chen CJ, Horlacher OC, Winkler S, John T, Browning J, MacGregor D, Cebon J, Dunbar PR (2009) Distinctive localization of antigen-presenting cells in human lymph nodes. Blood 113(6):1257–1267. doi:10.1182/blood-2008-06-165266

    Article  PubMed  CAS  Google Scholar 

  25. Liu J, Lu G, Li Z, Tang F, Liu Y, Cui G (2010) Distinct compartmental distribution of mature and immature dendritic cells in esophageal squamous cell carcinoma. Pathol Res Pract 206(9):602–606. doi:10.1016/j.prp.2010.03.011

    Article  PubMed  CAS  Google Scholar 

  26. Cochran AJ, Morton DL, Stern S, Lana AM, Essner R, Wen DR (2001) Sentinel lymph nodes show profound downregulation of antigen-presenting cells of the paracortex: implications for tumor biology and treatment. Mod Pathol 14(6):604–608

    Article  PubMed  CAS  Google Scholar 

  27. Essner R, Kojima M (2002) Dendritic cell function in sentinel nodes. Oncology (Williston Park) 16(1 Suppl 1):27–31

    Google Scholar 

  28. Polak ME, Johnson P, Di Palma S, Higgins B, Hurren J, Borthwick NJ, Jager MJ, McCormick D, Cree IA (2005) Presence and maturity of dendritic cells in melanoma lymph node metastases. J Pathol 207(1):83–90

    Article  PubMed  Google Scholar 

  29. Polak ME, Borthwick NJ, Gabriel FG, Johnson P, Higgins B, Hurren J, McCormick D, Jager MJ, Cree IA (2007) Mechanisms of local immunosuppression in cutaneous melanoma. Br J Cancer 96(12):1879–1887

    Article  PubMed  CAS  Google Scholar 

  30. Gerlini G, Urso C, Mariotti G, Di Gennaro P, Palli D, Brandani P, Salvadori A, Pimpinelli N, Reali UM, Borgognoni L (2007) Plasmacytoid dendritic cells represent a major dendritic cell subset in sentinel lymph nodes of melanoma patients and accumulate in metastatic nodes. Clin Immunol 125(2):184–193. doi:10.1016/j.clim.2007.07.018

    Article  PubMed  CAS  Google Scholar 

  31. Campbell MJ, Scott J, Maecker HT, Park JW, Esserman LJ (2005) Immune dysfunction and micrometastases in women with breast cancer. Breast Cancer Res Treat 91(2):163–171. doi:10.1007/s10549-004-7048-0

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Eija Heiliö for her assistance with immunohistochemistry. The Helsinki University Central Hospital Research Fund provided funding for this work.

Conflicts of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland

    Aaron Scott Mansfield, Karl von Smitten & Marjut Leidenius

  2. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland

    Paivi Heikkila

  3. Hematology Research Unit, Helsinki University Central Hospital, Helsinki, Finland

    Jukka Vakkila

  4. Division of Hematology, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA

    Aaron Scott Mansfield

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  1. Aaron Scott Mansfield
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  2. Paivi Heikkila
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  3. Karl von Smitten
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  5. Marjut Leidenius
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Correspondence to Aaron Scott Mansfield.

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Mansfield, A.S., Heikkila, P., von Smitten, K. et al. Metastasis to sentinel lymph nodes in breast cancer is associated with maturation arrest of dendritic cells and poor co-localization of dendritic cells and CD8+ T cells. Virchows Arch 459, 391–398 (2011). https://doi.org/10.1007/s00428-011-1145-3

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  • DOI: https://doi.org/10.1007/s00428-011-1145-3

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