Skip to main content

Advertisement

Springer Nature Link
Log in

Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Various clinical and experimental observations detected an immunological host defense in cutaneous melanoma. In order to investigate the prognostic value of leukocyte effector mechanisms, we examined the presence of different subsets of leukocytes in tumor samples of 58 patients diagnosed with primary cutaneous melanoma. The presence of T lymphocytes, cytotoxic T lymphocytes, B lymphocytes, CD16+ cells and macrophages was correlated to Breslow depth. A significantly higher amount of several subsets of leukocytes was found in samples with a more progressed tumor stage and survival analysis demonstrated that a higher amount of T lymphocytes and CD16+ cells was associated with a short survival. The amount of FOXP3+ regulatory T lymphocytes did not correlate with survival, nevertheless, it correlated with the amount of total infiltrate. In contrast, analysis of the expression of CD69, a marker for activated lymphocytes, demonstrated that patients with a higher amount of CD69+ lymphocytes had a better survival. In addition, a new parameter for aggressiveness of melanoma, tumor cell plasticity [i.e., the presence of periodic acid Schiff’s (PAS) reagent positive loops], also predicted short survival and a trend of a higher amount of tumor infiltrating leukocytes in tumors with PAS positive loops was observed. These findings demonstrate that leukocyte infiltration and the presence of PAS loops is a sign of tumor aggressiveness and may have prognostic value.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ramirez-Montagut T, et al (2003) Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity. Oncogene 22(20):3180–3187

    Article  PubMed  CAS  Google Scholar 

  2. Chen Q, Wang WC, Evans SS (2003) Tumor microvasculature as a barrier to antitumor immunity. Cancer Immunol Immunother 52(11):670–679

    Article  PubMed  Google Scholar 

  3. Vesalainen S, et al (1994) Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur J Cancer 30A(12):1797–1803

    Article  PubMed  CAS  Google Scholar 

  4. Marrogi AJ, et al (1997) Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma. Int J Cancer 74(5):492–501

    Article  PubMed  CAS  Google Scholar 

  5. Chao HT, et al (1999) Lymphocyte-infiltrated FIGO Stage IIB squamous cell carcinoma of the cervix is a prominent factor for disease-free survival. Eur J Gynaecol Oncol 20(2):136–140

    PubMed  CAS  Google Scholar 

  6. Naito Y, et al (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58(16):3491–3494

    PubMed  CAS  Google Scholar 

  7. Schumacher K, et al (2001) Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 61(10):3932–3936

    PubMed  CAS  Google Scholar 

  8. Cho Y, et al (2003) CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res 63(7):1555–1559

    PubMed  CAS  Google Scholar 

  9. Zhang L, et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213

    Article  PubMed  CAS  Google Scholar 

  10. Sato E, et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543

    Article  PubMed  CAS  Google Scholar 

  11. Badoual C, et al (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12(2):465–472

    Article  PubMed  CAS  Google Scholar 

  12. Hiraoka K, et al (2006) Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 94(2):275–280

    Article  PubMed  CAS  Google Scholar 

  13. Hussein MR (2005) Tumour-infiltrating lymphocytes and melanoma tumorigenesis: an insight. Br J Dermatol 153(1):18–21

    Article  PubMed  CAS  Google Scholar 

  14. Clark WH Jr, et al (1989) Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81(24):1893–1904

    Article  PubMed  Google Scholar 

  15. Clemente CG, et al (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77(7):1303–1310

    Article  PubMed  CAS  Google Scholar 

  16. Thorn M, et al (1994) Trends in tumour characteristics and survival of malignant melanoma 1960–84: a population-based study in Sweden. Br J Cancer 70(4):743–748

    PubMed  CAS  Google Scholar 

  17. Barnhill RL, et al (1996) Predicting five-year outcome for patients with cutaneous melanoma in a population-based study. Cancer 78(3):427–432

    Article  PubMed  CAS  Google Scholar 

  18. van der Schaft DW, et al (2005) Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res 65(24):11520–11528

    Article  PubMed  Google Scholar 

  19. Hillen F, et al (2006) Proliferating endothelial cells, but not microvessel density, is a prognostic parameter in human cutaneous melanoma. Melanoma Res 16:453–457

    Article  PubMed  Google Scholar 

  20. Warso MA, et al (2001) Prognostic significance of periodic acid-Schiff-positive patterns in primary cutaneous melanoma. Clin Cancer Res 7(3):473–477

    PubMed  CAS  Google Scholar 

  21. Hendrix MJ, et al (2003) Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3(6):411–421

    Article  PubMed  CAS  Google Scholar 

  22. Thies A, et al (2001) PAS-positive loops and networks as a prognostic indicator in cutaneous malignant melanoma. J Pathol 195(5):537–542

    Article  PubMed  CAS  Google Scholar 

  23. Levi F, et al (2004) Cancer mortality in Europe, 1995–1999, and an overview of trends since 1960. Int J Cancer 110(2):155–169

    Article  PubMed  CAS  Google Scholar 

  24. Carlson JA, et al (2003) Malignant melanoma 2003: predisposition, diagnosis, prognosis, and staging. Am J Clin Pathol 120(Suppl):S101–S127

    PubMed  Google Scholar 

  25. Eberlein TJ, Rosenstein M, Rosenberg SA (1982) Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2. J Exp Med 156(2):385–397

    Article  PubMed  CAS  Google Scholar 

  26. Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233(4770):1318–1321

    Article  PubMed  CAS  Google Scholar 

  27. Overwijk WW, et al (1998) gp100/pmel 17 is a murine tumor rejection antigen: induction of “self”-reactive, tumoricidal T cells using high-affinity, altered peptide ligand. J Exp Med 188(2):277–286

    Article  PubMed  CAS  Google Scholar 

  28. Dudley ME, et al (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594):850–854

    Article  PubMed  CAS  Google Scholar 

  29. Yee C, et al (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99(25):16168–16173

    Article  PubMed  CAS  Google Scholar 

  30. Dudley ME, et al (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23(10):2346–2357

    Article  PubMed  CAS  Google Scholar 

  31. Morgan RA, et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796):126–129

    Article  PubMed  CAS  Google Scholar 

  32. Hussein MR, et al (2006) Immunohistological characterisation of tumour infiltrating lymphocytes in melanocytic skin lesions. J Clin Pathol 59(3):316–324

    Article  PubMed  CAS  Google Scholar 

  33. Brocker EB, et al (1988) Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. Int J Cancer 41(4):562–567

    Article  PubMed  CAS  Google Scholar 

  34. Piras F, et al (2005) The predictive value of CD8, CD4, CD68, and human leukocyte antigen-D-related cells in the prognosis of cutaneous malignant melanoma with vertical growth phase. Cancer 104(6):1246–1254

    Article  PubMed  CAS  Google Scholar 

  35. Jorkov AS, et al (2003) Immune response in blood and tumour tissue in patients with metastatic malignant melanoma treated with IL-2, IFN alpha and histamine dihydrochloride. Anticancer Res 23(1B):537–542

    PubMed  CAS  Google Scholar 

  36. Jovic V, et al (2001) Impaired perforin-dependent NK cell cytotoxicity and proliferative activity of peripheral blood T cells is associated with metastatic melanoma. Tumori 87(5):324–329

    PubMed  CAS  Google Scholar 

  37. Mantovani A, et al (1992) The origin and function of tumor-associated macrophages. Immunol Today 13(7):265–270

    Article  PubMed  CAS  Google Scholar 

  38. Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196(3):254–265

    Article  PubMed  CAS  Google Scholar 

  39. Dirkx AEM, et al (2006) Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol 80(6):1183–1196

    Article  PubMed  CAS  Google Scholar 

  40. Bennett SR, et al (1998) B cells directly tolerize CD8(+) T cells. J Exp Med 188(11):1977–1983

    Article  PubMed  CAS  Google Scholar 

  41. Perricone MA, et al (2004) Enhanced efficacy of melanoma vaccines in the absence of B lymphocytes. J Immunother 27(4):273–281

    Article  PubMed  CAS  Google Scholar 

  42. Shah S, et al (2005) Increased rejection of primary tumors in mice lacking B cells: inhibition of anti-tumor CTL and TH1 cytokine responses by B cells. Int J Cancer 117(4):574–586

    Article  PubMed  CAS  Google Scholar 

  43. Lapointe R, et al (2003) CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells. Cancer Res 63(11):2836–2843

    PubMed  CAS  Google Scholar 

  44. Martinez-Escribano JA, et al (2003) Changes in the number of CD80(+), CD86(+), and CD28(+) peripheral blood lymphocytes have prognostic value in melanoma patients. Hum Immunol 64(8):796–801

    Article  PubMed  CAS  Google Scholar 

  45. Aklilu M, et al (2004) Depletion of normal B cells with rituximab as an adjunct to IL-2 therapy for renal cell carcinoma and melanoma. Ann Oncol 15(7):1109–1114

    Article  PubMed  CAS  Google Scholar 

  46. Massague J (1990) The transforming growth factor-beta family. Annu Rev Cell Biol 6:597–641

    Article  PubMed  CAS  Google Scholar 

  47. Fiorentino DF, et al (1991) IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol 146(10):3444–3451

    PubMed  CAS  Google Scholar 

  48. Ladanyi A, et al (2004) T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 10(2):521–530

    Article  PubMed  CAS  Google Scholar 

  49. Rubinstein N, et al (2004) Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege. Cancer Cell 5(3):241–251

    Article  PubMed  CAS  Google Scholar 

  50. Le QT, et al (2005) Galectin-1: a link between tumor hypoxia and tumor immune privilege. J Clin Oncol 23(35):8932–8941

    Article  PubMed  CAS  Google Scholar 

  51. Pawelec G (2004) Tumour escape from the immune response. Cancer Immunol Immunother 53(10):843

    Article  PubMed  CAS  Google Scholar 

  52. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    Article  PubMed  CAS  Google Scholar 

  53. Woo EY, et al (2001) Regulatory CD4(+) CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61(12):4766–4772

    PubMed  CAS  Google Scholar 

  54. Woo EY, et al (2002) Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168(9):4272–4276

    PubMed  CAS  Google Scholar 

  55. Sasada T, et al (2003) CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98(5):1089–1099

    Article  PubMed  Google Scholar 

  56. Wolf AM, et al (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9(2):606–612

    PubMed  Google Scholar 

  57. Viguier M, et al (2004) Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol 173(2):1444–1453

    PubMed  CAS  Google Scholar 

  58. Alvaro T, et al (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11(4):1467–1473

    Article  PubMed  Google Scholar 

  59. Wolf D, et al (2005) The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11(23):8326–8331

    Article  PubMed  CAS  Google Scholar 

  60. Hiraoka N, et al (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12(18):5423–5434

    Article  PubMed  CAS  Google Scholar 

  61. Bates GJ, et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24(34):5373–5380

    Article  PubMed  Google Scholar 

  62. Appay V, et al (2006) New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J Immunol 177(3):1670–1678

    PubMed  CAS  Google Scholar 

  63. Ahmadzadeh M, Rosenberg SA (2006) IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood 107(6):2409–2414

    Article  PubMed  CAS  Google Scholar 

  64. Nair S, et al (2007) Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 67(1):371–380

    Article  PubMed  CAS  Google Scholar 

  65. Cambiaggi C, et al (1992) Constitutive expression of CD69 in interspecies T-cell hybrids and locus assignment to human chromosome 12. Immunogenetics 36(2):117–120

    Article  PubMed  CAS  Google Scholar 

  66. Healy CG, et al (1998) Impaired expression and function of signal-transducing zeta chains in peripheral T cells and natural killer cells in patients with prostate cancer. Cytometry 32(2):109–119

    Article  PubMed  CAS  Google Scholar 

  67. Koch M, et al (2006) Tumor infiltrating T lymphocytes in colorectal cancer: tumor-selective activation and cytotoxic activity in situ. Ann Surg 244(6):986–992; discussion 992-3

    Article  PubMed  Google Scholar 

  68. Slingluff CL Jr, et al (1988) Lethal “thin” malignant melanoma. Identifying patients at risk. Ann Surg 208(2):150–161

    Google Scholar 

  69. Blessing K, McLaren KM (1992) Histological regression in primary cutaneous melanoma: recognition, prevalence and significance. Histopathology 20(4):315–322

    Article  PubMed  CAS  Google Scholar 

  70. Trau H, et al (1983) Metastases of thin melanomas. Cancer 51(3):553–556

    Article  PubMed  CAS  Google Scholar 

  71. Wanebo HJ, Cooper PH, Hagar RW (1985) Thin (less than or equal to 1 mm) melanomas of the extremities are biologically favorable lesions not influenced by regression. Ann Surg 201(4):499–504

    Article  PubMed  CAS  Google Scholar 

  72. Shaw HM, et al (1987) Thin malignant melanomas and recurrence potential. Arch Surg 122(10):1147–1150

    PubMed  CAS  Google Scholar 

  73. Fontaine D, et al (2003) Partial regression of primary cutaneous melanoma: is there an association with sub-clinical sentinel lymph node metastasis? Am J Dermatopathol 25(5):371–376

    Article  PubMed  Google Scholar 

  74. Molema G, Griffioen AW (1998) Rocking the foundations of solid tumor growth by attacking the tumor’s blood supply. Immunol Today 19(9):392–394

    Article  PubMed  CAS  Google Scholar 

  75. Maniotis AJ, et al (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155(3):739–752

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Angiogenesis Laboratory, Department of Pathology, Research Institute for Growth and Development (GROW), University Hospital Maastricht, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands

    Femke Hillen, Coen I. M. Baeten, Anouk van de Winkel, David Creytens, Daisy W. J. van der Schaft, Véronique Winnepenninckx & Arjan W. Griffioen

Authors
  1. Femke Hillen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Coen I. M. Baeten
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anouk van de Winkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Creytens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daisy W. J. van der Schaft
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Véronique Winnepenninckx
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Arjan W. Griffioen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arjan W. Griffioen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hillen, F., Baeten, C.I.M., van de Winkel, A. et al. Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 57, 97–106 (2008). https://doi.org/10.1007/s00262-007-0353-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-007-0353-9

Keywords

Search

Navigation