Skip to main content

Advertisement

SpringerLink
Log in

Defective levels of both circulating dendritic cells and T-regulatory cells correlate with risk of recurrence in cutaneous melanoma

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

Immune markers in the peripheral blood of melanoma patients provide useful information for clinical management although there is poor consensus on circulating cells which could putatively reflect the disease activity and play a prognostic role. Here, we investigated both dendritic cells (DCs) and T-regulatory cells (Tregs).

Methods

The number of DC subsets as myeloid (m) and plasmacytoid was measured by flowcytometry in 113 melanoma patients in different clinical stages and correlated with the disease activity to evaluate the recurrence free survival (RFS) calculated as difference between baseline and post-surgical values in relation to the criteria for the melanoma staging, as primary tumor removal, sentinel lymph node biopsy and completion of lymph node dissection.

Results

Circulating mDC levels were significantly lower in metastatic melanoma than in other stages and inversely correlated to Treg values while both populations were similarly expressed in inactive disease at stage I-III. Furthermore, the levels of these cells after melanoma removal were apparently related to the disease activity since their persistent defect reflected high risk of recurrence and reduced the RFS.

Conclusions

This work highlighted the role of immune cell measurement for the management of melanoma activity and the identification of patients at potential risk of recurrence based on the mDC ratio.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

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. Stiegel E, Xiong D, Ya J, Funchain P, Isakov R, Gastman B, et al. Prognostic value of sentinel lymph node biopsy according to Breslow thickness for cutaneous melanoma. J Am Acad Dermatol. 2018;78:942–8.

    Article  PubMed  Google Scholar 

  2. Gershenwald JE, Scolyer RA. Melanoma staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyond. Ann Surg Oncol. 2018;25:2105–10 (Springer International Publishing).

    Article  PubMed  Google Scholar 

  3. Pasquali S, Mocellin S, Mozzillo N, Maurichi A, Quaglino P, Borgognoni L, et al. Nonsentinel lymph node status in patients with cutaneous melanoma: results from a multi-institution prognostic study. J Clin Oncol. 2014;32:935–41.

    Article  PubMed  Google Scholar 

  4. Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17:757–67.

    Article  PubMed  Google Scholar 

  5. Tucci M, Stucci S, Passarelli A, Giudice G, Dammacco F, Silvestris F. The immune escape in melanoma: role of the impaired dendritic cell function. Expert Rev Clin Immunol. 2014;10:000 (Informa UK, Ltd).

    Article  CAS  Google Scholar 

  6. Chevolet I, Speeckaert R, Schreuer M, Neyns B, Krysko O, Bachert C, et al. Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma. OncoImmunology. 2015;4:e982382 (Taylor & Francis).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Damude S, Wevers KP, Murali R, Kruijff S, Hoekstra HJ, Bastiaannet E. A prediction tool incorporating the biomarker S-100B for patient selection for completion lymph node dissection in stage III melanoma. Eur J Surg Oncol. 2017;43:1753–9.

    Article  CAS  PubMed  Google Scholar 

  8. Damude S, Hoekstra HJ, Bastiaannet E, Muller Kobold AC, Kruijff S, Wevers KP. The predictive power of serum S-100B for non-sentinel node positivity in melanoma patients. Eur J Surg Oncol. 2016;42:545–51.

    Article  CAS  PubMed  Google Scholar 

  9. Weber J, Qureshi A, Ascierto PA. Adjuvant Therapy in Resected Melanoma. N Engl J Med. 2018;378:680 (Massachusetts Medical Society).

    Article  PubMed  Google Scholar 

  10. Galon J, Lugli A, Bifulco C, Pages F, Masucci G, Marincola FM, et al. World-wide immunoscore task force: meeting report from the “Melanoma Bridge”, Napoli, November 30th-December 3rd, 2016. J Transl Med. 2017;15:212. https://doi.org/10.1186/s12967-017-1310-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Failli A, Legitimo A, Orsini G, Romanini A, Consolini R. Numerical defect of circulating dendritic cell subsets and defective dendritic cell generation from monocytes of patients with advanced melanoma. Cancer Lett. 2013;337:184–92 (Elsevier Ireland Ltd).

    Article  CAS  PubMed  Google Scholar 

  12. McCarter MD, Baumgartner J, Escobar GA, Richter D, Lewis K, Robinson W, et al. Immunosuppressive dendritic and regulatory T cells are upregulated in melanoma patients. Ann Surg Oncol. 2007;14:2854–60 (Springer-Verlag).

    Article  PubMed  Google Scholar 

  13. Houot R, Perrot I, Garcia E, Durand I, Lebecque S. Human CD4 + CD25 high regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation. J Immunol Am Assoc Immunol. 2006;176:5293–8.

    CAS  Google Scholar 

  14. Gerlini G, Tun-Kyi A, Dudli C, Burg G, Pimpinelli N, Nestle FO. Metastatic melanoma secreted IL-10 down-regulates CD1 molecules on dendritic cells in metastatic tumor lesions. Am J Pathol. 2004;165:1853–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell. 2016;30:324–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chevolet I, Speeckaert R, Schreuer M, Neyns B, Krysko O, Bachert C, et al. Clinical significance of plasmacytoid dendritic cells and myeloid-derived suppressor cells in melanoma. J Transl Med. 2015;13:9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Legitimo A, Consolini R, Failli A, Orsini G, Spisni R. Dendritic cell defects in the colorectal cancer. Hum Vaccin Immunother. 2014;10:3224–35.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Verronèse E, Delgado A, Valladeau-Guilemond J, Garin G, Guillemaut S, Tredan O, et al. Immune cell dysfunctions in breast cancer patients detected through whole blood multi-parametric flow cytometry assay. OncoImmunology. 2016;5:1–15 (Taylor & Francis).

    Article  CAS  Google Scholar 

  19. Patin E, Hasan M, Bergstedt J, Rouilly V, Libri V, Urrutia A, et al. Publisher Correction: natural variation in the parameters of innate immune cells is preferentially driven by genetic factors. Nat Immunol. 2018;19:645–55 (Nature Publishing Group).

    Article  CAS  PubMed  Google Scholar 

  20. Mannavola F, Tucci M, Felici C, Stucci S, Silvestris F. miRNAs in melanoma: a defined role in tumor progression and metastasis. Expert Rev Clin Immunol. 2015;12:79–89.

    Article  CAS  PubMed  Google Scholar 

  21. Lombardi VC, Khaiboullina SF, Rizvanov AA. Plasmacytoid dendritic cells, a role in neoplastic prevention and progression. Eur J Clin Invest. 2014;45:1–8.

    Article  CAS  Google Scholar 

  22. Gerlini G, Urso C, Mariotti G, Di Gennaro P, Palli D, Brandani P, et al. Plasmacytoid dendritic cells represent a major dendritic cell subset in sentinel lymph nodes of melanoma patients and accumulate in metastatic nodes. Clin Immunol. 2007;125:184–93.

    Article  CAS  PubMed  Google Scholar 

  23. Orsini G, Legitimo A, Failli A, Ferrari P, Nicolini A, Spisni R, et al. Defective generation and maturation of dendritic cells from monocytes in colorectal cancer patients during the course of disease. IJMS. 2013;14:22022–41.

    Article  CAS  PubMed  Google Scholar 

  24. Bekeredjian-Ding I, Schäfer M, Hartmann E, Pries R, Parcina M, Schneider P, et al. Tumour-derived prostaglandin E and transforming growth factor-beta synergize to inhibit plasmacytoid dendritic cell-derived interferon-alpha. Immunology. 2009;128:439–50 (10.1111, Wiley/Blackwell).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tucci M, Quatraro C, Lombardi L, Pellegrino C, Dammacco F, Silvestris F. Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum. 2008;58:251–62.

    Article  CAS  PubMed  Google Scholar 

  26. Di Domizio J, Demaria O, Gilliet M. Plasmacytoid dendritic cells in melanoma: can we revert bad into good? J Invest Dermatol. 2014;134:1797–800.

    Article  CAS  PubMed  Google Scholar 

  27. Charles J, Di Domizio J, Salameire D, Bendriss-Vermare N, Aspord C, Muhammad R, et al. Characterization of circulating dendritic cells in melanoma: role of CCR6 in plasmacytoid dendritic cell recruitment to the tumor. J Invest Dermatol. 2010;130:1646–56.

    Article  CAS  PubMed  Google Scholar 

  28. Salio M, Cella M, Vermi W, Facchetti F, Palmowski MJ, Smith CL, et al. Plasmacytoid dendritic cells prime IFN-gamma-secreting melanoma-specific CD8 lymphocytes and are found in primary melanoma lesions. Eur J Immunol. 2003;33:1052–62 (Wiley-Blackwell).

    Article  CAS  PubMed  Google Scholar 

  29. Passarelli A, Mannavola F, Stucci LS, Tucci M, Silvestris F. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget. 2017;8:106132–42.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hussein MR. Dendritic cells and melanoma tumorigenesis: an insight. Cancer Biol Ther. 2005;4:501–5.

    Article  CAS  PubMed  Google Scholar 

  31. Bol KF, Schreibelt G, Gerritsen WR, de Vries IJM, Figdor CG. Dendritic cell-based immunotherapy: state of the art and beyond. Clin Cancer Res Am Assoc Can Res. 2016;22:1897–906.

    Article  CAS  Google Scholar 

  32. Gjorup CA, Groenvold M, Hendel HW, Dahlstroem K, Drzewiecki KT, Klausen TW, et al. Health-related quality of life in melanoma patients: impact of melanoma-related limb lymphoedema. Eur J Cancer. 2017;85:122–32.

    Article  PubMed  Google Scholar 

  33. Madu MF, Wouters MWJM, van Akkooi ACJ. Sentinel node biopsy in melanoma: current controversies addressed. Eur J Surg Oncol. 2017;43:517–33.

    Article  CAS  PubMed  Google Scholar 

  34. Mohos A, Sebestyén T, Liszkay G, Plótár V, Horváth S, Gaudi I, et al. Immune cell profile of sentinel lymph nodes in patients with malignant melanoma—FOXP3 + cell density in cases with positive sentinel node status is associated with unfavorable clinical outcome. J Transl Med BioMed Cent. 2013;11:43.

    Article  CAS  Google Scholar 

  35. Ladányi A, Kiss J, Somlai B, Gilde K, Fejos Z, Mohos A, 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. 2007;56:1459–69 (Springer-Verlag).

    Article  PubMed  Google Scholar 

  36. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23 (Massachusetts Medical Society).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by a Grant (#173536) from AIRC (Italian Association for Cancer Research).

Author information

Authors and Affiliations

  1. Section of Oncology, Department of Biomedical Sciences and Clinical Oncology, University of Bari ‘Aldo Moro’, P.za Giulio Cesare, 11, 70124, Bari, Italy

    M. Tucci, L. S. Stucci, F. Mannavola, A. Passarelli, S. D’Oronzo & F. Silvestris

  2. Section of Dermatology, Department of Biomedical Sciences and Clinical Oncology, University of Bari ‘Aldo Moro’, Bari, Italy

    L. Lospalluti

  3. Section of Plastic and Reconstructive Surgery, Department of Emergency and Organ Transplantation, University of Bari ‘Aldo Moro’, Bari, Italy

    G. Giudice

Authors
  1. M. Tucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. S. Stucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Mannavola
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Passarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. D’Oronzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Lospalluti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. Giudice
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Silvestris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Tucci.

Ethics declarations

Conflict of interest

The authors disclose financial conflict of interest.

Ethical approval

This study was approved by the Local Ethic Committee (protocol 4387/14).

Informed consent

Written consent was obtained from all patients.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tucci, M., Stucci, L.S., Mannavola, F. et al. Defective levels of both circulating dendritic cells and T-regulatory cells correlate with risk of recurrence in cutaneous melanoma. Clin Transl Oncol 21, 845–854 (2019). https://doi.org/10.1007/s12094-018-1993-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-018-1993-2

Keywords

Search

Navigation