List volumes - List articles in this issue

Investigative Report

Comparison of Foxp3+ Regulatory T cells and CD163+ Macrophages in Invasive and Non-invasive Extramammary Paget’s Disease

doi: 10.2340/00015555-1453


Regulatory T cells (Tregs), identified by the expression of CD4, CD25 and Foxp3, together with immunosuppressive macrophages, such as CD163+ M2 macrophages, are involved in maintaining peripheral tolerance. The aim of this study was to elucidate the involvement of Tregs and CD163+ macrophages in invasive and non-invasive extramammary Paget’s disease. The presence of CD4+CD25+Foxp3+ Tregs, CD163+ M2 macrophages and matrix metalloproteinase-9+ cells was examined immunohistologically in fixed sections of lesional skin from 10 patients with non-invasive extramammary Paget’s disease and 7 patients with invasive extramammary Paget’s disease. Fewer CD4+CD25+Foxp3+ Tregs were observed in non-invasive extramammary Paget’s disease than in invasive extramammary Paget’s disease. In contrast, higher numbers of CD163+ macrophages and metalloproteinase-9+ cells were detected only in invasive extramammary Paget’s disease. These findings suggest that the induction of immunosuppressive cells in extramammary Paget’s disease differs according to the tumour stage.


Taku Fujimura, Yumi Kambayashi, Takanori Hidaka, Akira Hashimoto, Takahiro Haga, Setsuya Aiba
Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan. E-mail:


1. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6: 345–352.

2. Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999; 163: 5211–5218.

3. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001; 182: 18–32.

4. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer 2010; 127: 759–767.

5. Viguier M, Lemaître F, Verola O, Cho MS, Gorochov G,Dubertret L, et al. Foxp3 expression CD4+CD25 high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immmunol 2004; 173: 1444–1453.

6. Fujimura T, Mahnke K, Enk AH. Myeloid derived suppressor cells and their role in tolerance induction in cancer. J Dermatol Sci 2010; 59: 1–6.

7. Pettersen JS, Fuentes-Duculan J, Suárez-Fariñas M, Pierson KC, Pitts-Kiefer A, Fan L, et al. Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated. J Invest Dermatol 2011; 131: 1322–1330.

8. Tjiu JW, Chen JS, Shun CT, Lin SJ, Liao YH, Chu CY, et al. Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Invest Dermatol 2011; 129: 1016–1025.

9. Jang TJ. Prevalence of Foxp3 positive T regulatory cells is increased during progression of cutaneous squamous tumors. Yonsei Med 2008; 49: 942–948.

10. Fujimura T, Okuyama R, Ito Y, Aiba S. Profiles of Foxp3+ regulatory T cells in eczematous dermatitis, psoriasis vulgaris and mycosis fungoides. Br J Dermatol 2008; 158: 1256–1263.

11. Press JZ, Allison KH, Garcia R, Everett EN, Pizer E, Swensen RE, et al. FOXP3+ regulatory T-cells are abundant in vulvar Paget’s disease and are associated with recurrence. Gynecol Oncol 2011; 120: 296–299.

12. Mahnke K, Johnson TS, Ring S, Enk AH. Tolerogeneic dendritic cells and regulatory T cells: a two-way relationship. J Dermatol Sci 2007; 46: 159–167.

13. André S, Tough DF, Lacroix-Desmazes S, Kaveri SV, Bayry J. Surveillance of antigen-presenting cells by CD4+CD25+ regulatory T cells in autoimmunity. Am J Pathol 2009; 174: 1575–1587.

14. Mahnke K, Ring S, Johnson TS, Schallenberg S, Schönfeld K, Storn V, et al. Induction of immunosuppressive functions of dendritic cells in vivo by CD4+CD25+ regulatory T cells: Role of B7-H3 expression and antigen presentation. Eur J Immunol 2007; 37: 2117–2126.

15. Fujimura T, Ring S, Umansky V, Mahnke K, Enk AH. Regulatory T cells (Treg) stimulate B7-H1 expression in myeloid derived suppressor cells (MDSC) in ret melanomas. J Invest Dermatol 2012; 132: 1239–1246.

16. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of Kit-ligand. Cell 2002; 109: 625–637.

17. Vihinen PP, Hernberg M, Vuoristo MS, Tyynelä K, Laukka M, Lundin J, et al. A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-alpha2a as first line treatment in metastatic melanoma. Melanoma Res 2010; 20: 318–325.

18. Zhang G, Luo X, Sumithran E, Pua VS, Barnetson RS, Halliday GM, Khachigian LM. Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression. Oncogene 2006; 25: 7260–7266.

19. Monhian N, Jewett BS, Baker SR, Varani J. Matrix metalloproteinase expression in normal skin associated with basal cell carcinoma and in distal skin from the same patients. Arch Facial Plast Surg 2005; 7: 238–243.

20. Rasheed H, Tolba Fawzi MM, Abdel-Halim MR, Eissa AM, Mohammed Salem N, Mahfouz S. Immunohistochemical study of the expression of matrix metalloproteinase-9 in skin lesions of mycosis fungoides. Am J Dermatopathol 2010; 32: 162–169.

21. Ishibashi M, Fujimura T, Hashimoto A, Haga T, Onami K, Tsukada A, et al. Successful treatment of MMP9-expressing angiosarcoma with low-dose docetaxel and biphosphonate. Case Rep Dermatol 2012; 4: 5–9.

22. Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res 2007; 67: 11438–11446.

23. Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 2007; 110: 2983–2990.

24. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009; 30: 899–911.

25. Fujii H, Arakawa A, Kitoh A, Miyara M, Kato M, Kore-eda S, et al. Perturbations of both nonregulatory and regulatory FOXP3+T cells in patients with malignant melanoma. Br J Dermatol 2011; 164: 1052–1060.

Related articles

There are no related articles.

Share with your friends



Full text



Figure S1

Print information

Volume 92, Issue 6

DOI: 10.2340/00015555-1453

Pages: 625-628

View at PubMed