Skip to main content

Advertisement

Log in

Langerhans, plasmacytoid dendritic and myeloid-derived suppressor cell levels in mycosis fungoides vary according to the stage of the disease

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Mycosis fungoides (MF) is characterized by a switch from indolent behaviour in the early stages to a worse clinical outcome in the advanced ones. Recently, various studies have investigated the role the microenvironment might play in such a switch. We have analysed the distribution of Langerhans cells, plasmacytoid dendritic cells and myeloid-derived suppressor cells in 46 MF cases in various stages, aiming to assess whether changes occur from early to advanced stage. We have investigated the number of langerin, CD303 and arginase-1 positive cells and their distribution at high power. Data were analysed using t test for continuous variables, χ 2 tests or Fisher’s exact test for categorical variables, as well as analysis of covariance. In comparing stages IA/B to IIB, we observed a significant decrease in Langerhans cells (p value 0.03) and a significant increase in CD303 and arginase-1 positive cells (p value <0.01 for both markers). Furthermore, a significant increase in Langerhans cells only was observed in stage IIB in comparison to stage III (p = 0.02), while in stage IV, a significant decrease in Langerhans cells was noted in comparison to stage III (p = 0.02). Our data suggest that changes in the microenvironment might influence disease progression, especially from stages IA/B to IIB, opening new scenarios in MF therapy.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pileri A Jr, Patrizi A, Agostinelli C et al (2011) Primary cutaneous lymphomas: a reprisal. Semin Diagn Pathol 28:214–233

    Article  PubMed  Google Scholar 

  2. Quaglino P, Pimpinelli N, Berti E et al (2012) Mycosis fungoides: disease evolution of the “lion queen” revisited. G Ital Dermatol Venereol 147:523–531

    CAS  PubMed  Google Scholar 

  3. Scarisbrick JJ, Prince HM, Vermeer MH et al (2015) Cutaneous lymphoma international consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model. J Clin Oncol 33:3766–3773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pimpinelli N, Olsen EA, Santucci M et al (2005) Defining early mycosis fungoides. J Am Acad Dermatol 53:1053–1063

    Article  PubMed  Google Scholar 

  5. Cerroni L (2006) Lymphoproliferative lesions of the skin. J Clin Pathol 59:813–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wong HK, Mishra A, Hake T et al (2011) Evolving insights in the pathogenesis and therapy of cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome). Br J Haematol 155:150–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wilcox RA (2016) Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 91:151–165

    Article  CAS  PubMed  Google Scholar 

  8. Dunn GP, Old LJ, Schreiber RD (2004a) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360

    Article  CAS  PubMed  Google Scholar 

  9. Dunn GP, Bruce AT, Ikeda H et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998

    Article  CAS  PubMed  Google Scholar 

  10. Dunn GP, Old LJ, Schreiber RD (2004b) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148

    Article  CAS  PubMed  Google Scholar 

  11. Smyth MJ, Godfrey DI, Trapani JA (2001) A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2:293–299

    Article  CAS  PubMed  Google Scholar 

  12. Berger CL, Tigelaar R, Cohen J et al (2005) Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 105:1640–1647

    Article  CAS  PubMed  Google Scholar 

  13. Fried I, Cerroni L (2012) FOXP3 in sequential biopsies of progressive mycosis fungoides. Am J Dermatopathol 34:263–265

    Article  PubMed  Google Scholar 

  14. Goos M, Kaiserling E, Lennert K (1976) Mycosis fungoides: model for T-lymphocyte homing to the skin? Br J Dermatol 94:221–222

    Article  CAS  PubMed  Google Scholar 

  15. Pimpinelli N, Santucci M, Romagnoli P et al (1994) Dendritic cells in T- and B-cell proliferation in the skin. Dermatol Clin 12:255–270

    CAS  PubMed  Google Scholar 

  16. Lüftl M, Feng A, Licha E et al (2002) Dendritic cells and apoptosis in mycosis fungoides. Br J Dermatol 147:1171–1179

    Article  PubMed  Google Scholar 

  17. Der-Petrossian M, Valencak J, Jonak C et al (2011) Dermal infiltrates of cutaneous T-cell lymphomas with epidermotropism but not other cutaneous lymphomas are abundant with langerin+ dendritic cells. J Eur Acad Dermatol Venereol 25:922–927

    Article  CAS  PubMed  Google Scholar 

  18. Schlapbach C, Ochsenbein A, Kaelin U et al (2010) High numbers of DC-SIGN+ dendritic cells in lesional skin of cutaneous T-cell lymphoma. J Am Acad Dermatol 62:995–1004

    Article  PubMed  Google Scholar 

  19. Schwingshackl P, Obermoser G, Nguyen VA et al (2012) Distribution and maturation of skin dendritic cell subsets in two forms of cutaneous T-cell lymphoma: mycosis fungoides and Sézary syndrome. Acta Derm Venereol 92:269–275

    Article  CAS  PubMed  Google Scholar 

  20. Zhang QA, Chen ZQ, Chen MH et al (2014) The number of regular T cells and immature dendritic cells involved in mycosis fungoides is linked to the tumor stage. Eur Rev Med Pharmacol Sci 18:553–558

    PubMed  Google Scholar 

  21. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 9:162–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kumar V, Patel S, Tcyganov E et al (2016) The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37:208–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Youn JI, Gabrilovich DI (2010) The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 40:2969–2975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5:641–654

    Article  CAS  PubMed  Google Scholar 

  25. Rodríguez PC, Ochoa AC (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222:180–191

    Article  PubMed  PubMed Central  Google Scholar 

  26. Strauss L, Sangaletti S, Consonni FM et al (2015) RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell 28:253–269

    Article  CAS  PubMed  Google Scholar 

  27. Rodriguez PC, Hernandez CP, Quiceno D et al (2005) Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202:931–939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Serafini P, Mgebroff S, Noonan K et al (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68:5439–5449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang B, Pan PY, Li Q et al (2006) Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66:1123–1131

    Article  CAS  PubMed  Google Scholar 

  30. Pan PY, Ma G, Weber KJ et al (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70:99–108

    Article  CAS  PubMed  Google Scholar 

  31. Bunt SK, Yang L, Sinha P et al (2007) Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res 67:10019–10026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Srivastava MK, Sinha P, Clements VK et al (2010) Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 70:68–77

    Article  CAS  PubMed  Google Scholar 

  33. Hanson EM, Clements VK, Sinha P et al (2009) Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J Immunol 15(183):937–944

    Article  Google Scholar 

  34. Vardhana S, Younes A (2016) The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints. Haematologica 101:794–802

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wu AA, Drake V, Huang HS et al (2015) Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells. Oncoimmunology 4:e1016700

    Article  PubMed  PubMed Central  Google Scholar 

  36. Dette H, Neumeyer N (2001) Nonparametric analysis of covariance. Ann Stat 29:1361–1400

    Article  Google Scholar 

  37. Young SG, Bowman AW (1995) Non-parametric analysis of covariance. Biometrics 51:920–931

    Article  Google Scholar 

  38. Wang XF, Ye D (2010) On nonparametric comparison of images and regression surfaces. J Stat Plann Inference 140:2875–2884

    Article  Google Scholar 

  39. Gabrilovich D, Ishida T, Oyama T et al (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92:4150–4166

    CAS  PubMed  Google Scholar 

  40. Pileri A, Agostinelli C, Righi S et al (2015) Vascular endothelial growth factor A (VEGFA) expression in mycosis fungoides. Histopathology 66:173–181

    Article  PubMed  Google Scholar 

  41. Kim YH, Gratzinger D, Harrison C et al (2012) In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 119:355–363

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mauti LA, Le Bitoux MA, Baumer K et al (2011) Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation. J Clin Invest 121:2794–2807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mairhofer DG, Ortner D, Tripp CH et al (2015) Impaired gp100-specific CD8(+) T-cell responses in the presence of myeloid-derived suppressor cells in a spontaneous mouse melanoma model. J Invest Dermatol 135:2785–2793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pérez C, González-Rincón J, Onaindia A et al (2015) Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma. Haematologica 100:e450–e453

    Article  PubMed  PubMed Central  Google Scholar 

  45. Dufait I, Van Valckenborgh E, Menu E, et al. (2016) Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy. Oncotarget. [Epub ahead of print].

  46. Fava P, Bergallo M, Astrua C, et al. (2016) miR-155 expression in primary cutaneous T- cell lymphomas (CTCL). J Eur Acad Dermatol Venereol. [Epub ahead of print].

  47. Chen S, Zhang Y, Kuzel TM et al (2015) Regulating tumor myeloid-derived suppressor cells by microRNAs. Cancer Cell Microenviron 2:e637

    PubMed  PubMed Central  Google Scholar 

  48. Kim S, Song JH, Kim S et al (2016) Loss of oncogenic miR-155 in tumor cells promotes tumor growth by enhancing C/EBP-β-mediated MDSC infiltration. Oncotarget 7:11094–11112

    PubMed  PubMed Central  Google Scholar 

  49. Sasso MS, Lollo G, Pitorre M et al (2016) Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy. Biomaterials 96:47–62

    Article  CAS  PubMed  Google Scholar 

  50. He W, Liang P, Guo G et al (2016) Re-polarizing myeloid-derived suppressor cells (MDSCs) with cationic polymers for cancer immunotherapy. Sci Rep 6:24506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Campbell JJ, Clark RA, Watanabe R et al (2010) Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood 116:767–771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alessandro Pileri.

Ethics declarations

All the patients provided their consent to the study, which was approved by the local Review Board and was conducted in accordance with the Helsinki Declaration.

Funding sources

None.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pileri, A., Agostinelli, C., Sessa, M. et al. Langerhans, plasmacytoid dendritic and myeloid-derived suppressor cell levels in mycosis fungoides vary according to the stage of the disease. Virchows Arch 470, 575–582 (2017). https://doi.org/10.1007/s00428-017-2107-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-017-2107-1

Keywords

Navigation