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Density of DC-LAMP+ mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor

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Abstract

As the most potent antigen presenting cells, dendritic cells (DCs) play key roles in the immune response against tumors. Their density in the tumor tissue has been associated with prognosis in patients with various cancers. However, few studies have been aimed at the presence and maturation state of DCs in cutaneous melanoma, with regard to their potential clinical correlates. In this study, the density of DCs expressing CD1a and the maturation marker DC-LAMP was determined by immunohistochemistry in primary tumor samples from 82 patients with cutaneous malignant melanoma. Intratumoral and peritumoral cell densities were analyzed in relation to tumor thickness and the subsequent development of metastases, as well as to patients’ survival. CD1a+ DCs were found both infiltrating melanoma cell nests and in the surrounding stroma, while DC-LAMP+ mature DCs were generally confined to the peritumoral areas, associated with lymphocytic infiltrates. DC density values significantly correlated with the number of activated (CD25+ or OX40+) T lymphocytes (p < 0.001). The degree of infiltration by CD1a+ and DC-LAMP+ DCs showed strong inverse correlation with the thickness of melanomas (p < 0.001). High peritumoral density of mature DCs was associated with significantly longer survival (p = 0.0195), while density of CD1a+ cells had a prognostic impact of borderline significance (p = 0.0610). Moreover, combination of high peritumoral CD1a+ or DC-LAMP+ cell density with high number of CD25+ or OX40+ lymphocytes identified patient subgroups with more favorable survival compared to other subgroups. A multivariate survival analysis involving DC and activated T-cell densities alone and in combinations, as well as traditional prognostic factors, identified high DC-LAMP+ cell/high OX40+ cell density and Breslow index as independent predictors of good prognosis. These results suggest that the presence of CD1a+ DCs primarily depends on the thickness of melanomas, without direct relationship with the patients’ survival. On the other hand, the density of mature DCs, especially in association with that of activated T cells, proved of prognostic importance, suggesting that these parameters could be considered as signs of a functional immune response associated with better outcome of the disease.

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References

  1. Albert ML, Jegathesan M, Darnell RB (2001) Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells. Nat Immunol 2:1010–1017

    Article  PubMed  CAS  Google Scholar 

  2. Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6:1755–1766

    PubMed  CAS  Google Scholar 

  3. Ambe K, Mori M, Enjoji M (1989) S-100 protein-positive dendritic cells in colorectal adenocarcinomas. Distribution and relation to the clinical prognosis. Cancer 63:496–503

    Article  PubMed  CAS  Google Scholar 

  4. Balch CM, Buzaid AC, Soong S-J, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648

    PubMed  CAS  Google Scholar 

  5. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  PubMed  CAS  Google Scholar 

  6. Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, Valladeau J, Davoust J, Palucka KA, Banchereau J (1999) In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 190:1417–1425

    Article  PubMed  CAS  Google Scholar 

  7. Bröcker EB, Zwadlo G, Holzmann B, Macher E, Sorg C (1988) Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. Int J Cancer 41:562–567

    Article  PubMed  Google Scholar 

  8. Cella M, Sallusto F, Lanzavecchia A (1997) Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol 9:10–16

    Article  PubMed  CAS  Google Scholar 

  9. Chaux P, Moutet M, Faivre J, Martin F, Martin M (1996) Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7-1 and B7-2 costimulatory molecules of the T-cell activation. Lab Invest 74:975–983

    PubMed  CAS  Google Scholar 

  10. Conrad CT, Ernst NR, Dummer W, Bröcker EB, Becker JC (1999) Differential expression of transforming growth factor beta 1 and interleukin 10 in progressing and regressing areas of primary melanoma. J Exp Clin Cancer Res 18:225–232

    PubMed  CAS  Google Scholar 

  11. 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 9:325–336

    Article  PubMed  Google Scholar 

  12. Enk AH, Jonuleit H, Saloga J, Knop J (1997) Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer 73:309–316

    Article  PubMed  CAS  Google Scholar 

  13. Esche C, Lokshin A, Shurin GV, Gastman BR, Rabinowich H, Watkins SC, Lotze MT, Shurin MR (1999) Tumor’s other immune targets: dendritic cells. J Leukoc Biol 66:336–344

    PubMed  CAS  Google Scholar 

  14. Facchetti F, Vermi W, Mason D, Colonna M (2003) The plasmacytoid monocyte/interferon producing cells. Virchows Arch 443:703–717

    Article  PubMed  Google Scholar 

  15. Fullen DR, Headington JT (1998) Factor XIIIa-positive dermal dendritic cells and HLA-DR expression in radial versus vertical growth-phase melanomas. J Cutan Pathol 25:553–558

    Article  PubMed  CAS  Google Scholar 

  16. Gabrilovich DI, Chen HL, Girgis KR, Cunningham T, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103

    Article  PubMed  CAS  Google Scholar 

  17. Gabrilovich DI, Ciernik F, Carbone DP (1996) Dendritic cells in antitumor immune responses I. Defective antigen presentation in tumor-bearing hosts. Cell Immunol 170:101–110

    Article  PubMed  CAS  Google Scholar 

  18. Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP (1997) Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 3:483–490

    PubMed  CAS  Google Scholar 

  19. Geissmann F, Revy P, Regnault A, Lepelletier Y, Dy M, Brousse N, Amigorena S, Hermine O, Durandy A (1999) TGF-β1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 162:4567–4575

    PubMed  CAS  Google Scholar 

  20. Inoshima N, Nakanishi Y, Minami T, Izumi M, Takayama K, Yoshino I, Hara N (2002) The influence of dendritic cell infiltration and vascular endothelial growth factor expression on the prognosis of non-small cell lung cancer. Clin Cancer Res 8:3480–3486

    PubMed  CAS  Google Scholar 

  21. Ishigami S, Aikou T, Natsugoe S, Hokita S, Iwashige H, Tokushige M, Sonoda S (1998) Prognostic value of HLA-DR expression and dendritic cell infiltration in gastric cancer. Oncology 55:65–69

    Article  PubMed  CAS  Google Scholar 

  22. Ishigami S, Natsugoe S, Matsumoto M, Okumura H, Sakita H, Nakashima S, Takao S, Aikou T (2003) Clinical implications of intratumoral dendritic cell infiltration in esophageal squamous cell carcinoma. Oncol Rep 10:1237–1240

    PubMed  Google Scholar 

  23. Iwamoto M, Shinohara H, Miyamoto A, Okuzawa M, Mabuchi H, Nohara T, Gon G, Toyoda M, Tanigawa N (2003) Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas. Int J Cancer 104:92–97

    Article  PubMed  CAS  Google Scholar 

  24. Ladányi A, Somlai B, Gilde K, Fejös Z, Gaudi I, Tímár J (2004) T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 10:521–530

    Article  PubMed  Google Scholar 

  25. Lenz A, Heine M, Schuler G, Romani N (1993) Human and murine dermis contain dendritic cells. J Clin Invest 92:2587–2596

    PubMed  CAS  Google Scholar 

  26. Lutz M, Schuler G (2002) Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 23:445–449

    Article  PubMed  CAS  Google Scholar 

  27. 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 80:477–483

    Article  PubMed  Google Scholar 

  28. McLellan AD, Heiser A, Sorg RV, Fearnley DB, Hart DNJ (1998) Dermal dendritic cells associated with T lymphocytes in normal human skin display an activated phenotype. J Invest Dermatol 111:841–849

    Article  PubMed  CAS  Google Scholar 

  29. Movassagh M, Spatz A, Davoust J, Lebecque S, Romero P, Pittet M, Rimoldi D, Liénard D, Gugerli O, Ferradini L, Robert C, Avril M-F, Zitvogel L, Angevin E (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 Res 64:2192–2198

    Article  PubMed  CAS  Google Scholar 

  30. Péguet-Navarro J, Sportouch M, Popa I, Berthier O, Schmitt D, Portoukalian J (2003) Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis. J Immunol 170:3488–3494

    PubMed  Google Scholar 

  31. Reichert TE, Scheuer C, Day R, Wagner W, Whiteside TL (2001) The number of intratumoral dendritic cells and ζ-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer 91:2136–2147

    Article  PubMed  CAS  Google Scholar 

  32. Scarpino S, Stoppacciaro A, Ballerini F, Marchesi M, Prat M, Stella C, Sozzani S, Allavena P, Mantovani A, Ruco LP (2000) Papillary carcinoma of the thyroid: Hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells. Am J Pathol 156:831–837

    PubMed  CAS  Google Scholar 

  33. Shortman K, Liu Y-J (2002) Mouse and human dendritic cell subtypes. Nat Rev Immunol 21:151–161

    Article  Google Scholar 

  34. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, Antonenko S, Liu Y-J (1999) The nature of the principal type 1 interferon-producing cells in human blood. Science 284:1835–1837

    Article  PubMed  CAS  Google Scholar 

  35. Steinbrink K, Jonuleit H, Müller G, Schuler G, Knop J, Enk AH (1999) Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8+ T cells resulting in a failure to lyse tumor cells. Blood 93:1634–1642

    PubMed  CAS  Google Scholar 

  36. Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711

    Article  PubMed  CAS  Google Scholar 

  37. Stene MA, Babajanians M, Bhuta S, Cochran AJ (1988) Quantitative alterations in cutaneous Langerhans cells during the evolution of malignant melanoma of the skin. J Invest Dermatol 91:125–128

    Article  PubMed  CAS  Google Scholar 

  38. Suzuki A, Masuda A, Nagata H, Kameoka S, Kikawada Y, Yamakawa M, Kasajima T (2002) Mature dendritic cells make clusters with T cells in the invasive margin of colorectal carcinoma. J Pathol 196:37–43

    Article  PubMed  Google Scholar 

  39. Tazi A, Bouchonnet F, Grandsaigne M, Boumsell L, Hance AJ, 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. J Clin Invest 91:566–576

    Article  PubMed  CAS  Google Scholar 

  40. Toriyama K, Wen D-R, Paul E, Cochran AJ (1993) Variations in the distribution, frequency, and phenotype of Langerhans cells during the evolution of malignant melanoma of the skin. J Invest Dermatol 100:269S–273S

    Article  PubMed  CAS  Google Scholar 

  41. Troy AJ, Summers KL, Davidson PJT, Atkinson CH, Hart DNJ (1998) Minimal recruitment and activation of dendritic cells within renal cell carcinoma. Clin Cancer Res 4:585–593

    PubMed  CAS  Google Scholar 

  42. Udey MC (2004) Skin dendritic cells in immunity and autoimmunity. J Invest Dermatol Symp Proc 9:15–17

    Article  Google Scholar 

  43. Vandenabeele S, Wu L (1999) Dendritic cell origins: puzzles and paradoxes. Immunol Cell Biol 77:411–419

    Article  PubMed  CAS  Google Scholar 

  44. Vermi W, Bonecchi R, Facchetti F, Bianchi D, Sozzani S, Festa S, Berenzi A, Cella M, Colonna M (2003) Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J Pathol 200:255–268

    Article  PubMed  Google Scholar 

  45. Vuylsteke RJCLM, Molenkamp BG, Gietema HA, van Leeuwen PAM, Wijnands PGJTB, Vos W, van Diest PJ, Scheper RJ, Meijer S, de Gruijl TD (2004) Local administration of granulocyte/macrophage colony-stimulating factor increases the number and activation state of dendritic cells in the sentinel lymph node of early-stage melanoma. Cancer Res 64:8456–8460

    Article  PubMed  CAS  Google Scholar 

  46. Zhou LJ, Tedder TF (1995) Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily. J Immunol 154:3821–3835

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Katalin Derecskei, Violetta Piurkó and Miklós Kónya (National Institute of Oncology) for their excellent technical assistance, and to Eric Angevin (Institut Gustave-Roussy, Villejuif, France) for helpful suggestions. The study was supported by Hungarian Ministry of Health grant ETT 308/2003, grants GVOP-3.11.-2004-05-0090.3.0 and NKFP1a-0024-05.

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Authors and Affiliations

  1. Department of Tumor Progression, National Institute of Oncology, 7-9 Ráth György u., Budapest, H-1122, Hungary

    Andrea Ladányi & József Tímár

  2. Department of Dermatology, National Institute of Oncology, Budapest, Hungary

    Judit Kiss, Katalin Gilde & Zsuzsanna Fejős

  3. National Cancer Registry, National Institute of Oncology, Budapest, Hungary

    István Gaudi

  4. Institute of Dermato-Venerology, Semmelweis University, Budapest, Hungary

    Beáta Somlai

  5. 1st Institute of Pathology, Semmelweis University, Budapest, Hungary

    Anita Mohos

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  1. Andrea Ladányi
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Correspondence to Andrea Ladányi.

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Ladányi, A., Kiss, J., Somlai, B. 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). https://doi.org/10.1007/s00262-007-0286-3

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