Skip to main content

Advertisement

SpringerLink
Log in

Resistance to Apoptosis and Expansion of Regulatory T Cells in Relation to the Detection of Circulating Tumor Cells in Patients with Metastatic Epithelial Cancer

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Regulatory T cells may be crucial in the development of T cell tolerance to malignancies and contribute to immune dysfunctions. We investigated the percentage, activity, and onset of apoptosis of T cell subpopulations by multicolor flow cytometry in metastatic epithelial cancer patients compared to normal controls. Furthermore, a possible relationship between the presence of circulating tumor cells detected by immunocytochemistry and immune cell abnormalities was evaluated. Our study demonstrated a significantly elevated proportion of regulatory T cells in cancer patients (p < 0.001). In contrast to all other T cell subpopulations, regulatory T cells showed comparable Annexin V-binding characteristics in patients and normal controls. No relationship between the detection of circulating tumor cells and immune dysfunction was observed. These results indicate that cancer patients have a higher number of regulatory T cells with resistance to apoptotic stimuli partly responsible for immune dysfunctions as often observed in cancer patients.

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. Burnet FM. Immunological recognition of self. Science. 1961;133:307–11.

    Article  PubMed  CAS  Google Scholar 

  2. Houghton AN, Guevara-Patino JA. Immune recognition of self in immunity against cancer. J Clin Invest. 2004;114:468–71.

    PubMed  CAS  Google Scholar 

  3. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193:1285–94.

    Article  PubMed  CAS  Google Scholar 

  4. Fehervari Z, Sakaguchi S. CD4+ Tregs and immune control. J Clin Invest. 2004;114:1209–17.

    PubMed  CAS  Google Scholar 

  5. Shevach EM, McHugh RS, Piccirillo CA, Thornton AM. Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev. 2001;182:58–67.

    Article  PubMed  CAS  Google Scholar 

  6. Beissert S, Schwarz A, Schwarz T. Regulatory T cells. J Invest Dermatol. 2006;126:15–24.

    Article  PubMed  CAS  Google Scholar 

  7. Beyer M, Schultze JL. Regulatory T cells in cancer. Blood. 2006;108:804–11.

    Article  PubMed  CAS  Google Scholar 

  8. Graca L. New tools to identify regulatory T cells. Eur J Immunol. 2005;35:1678–80.

    Article  PubMed  CAS  Google Scholar 

  9. Baecher-Allan C, Anderson DE. Immune regulation in tumor-bearing hosts. Curr Opin Immunol. 2006;18:214–9.

    Article  PubMed  CAS  Google Scholar 

  10. Enarsson K, Lundin BS, Johnsson E, Brezicka T, Quiding-Jarbrink M. CD4(+)CD25(high) regulatory T cells reduce T cell transendothelial migration in cancer patients. Eur J Immunol. 2007;37:282–91.

    Article  PubMed  CAS  Google Scholar 

  11. Li H, Yu JP, Cao S, Wei F, Zhang P, An XM, Huang ZT, Ren XB. CD(4) (+)CD (25) (+) regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol. 2007;27:317–26.

    Article  PubMed  CAS  Google Scholar 

  12. 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;163:5211–8.

    PubMed  CAS  Google Scholar 

  13. Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J. Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci U S A. 2005;102:4091–6.

    Article  PubMed  CAS  Google Scholar 

  14. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61:4766–72.

    PubMed  CAS  Google Scholar 

  15. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–61.

    PubMed  CAS  Google Scholar 

  16. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res. 2003;9:606–12.

    PubMed  Google Scholar 

  17. Schaefer C, Kim GG, Albers A, Hoermann K, Myers EN, Whiteside TL. Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer. 2005;92:913–20.

    Article  PubMed  CAS  Google Scholar 

  18. Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H, Fujii H. CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother. 2006;55:1064–71.

    Article  PubMed  CAS  Google Scholar 

  19. Miller AM, Lundberg K, Ozenci V, Banham AH, Hellstrom M, Egevad L, Pisa P. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol. 2006;177:7398–405.

    PubMed  CAS  Google Scholar 

  20. Hoffmann TK, Dworacki G, Tsukihiro T, Meidenbauer N, Gooding W, Johnson JT, Whiteside TL. Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin Cancer Res. 2002;8:2553–62.

    PubMed  Google Scholar 

  21. Bauernhofer T, Kuss I, Friebe-Hoffmann U, Baum AS, Dworacki G, Vonderhaar BK, Whiteside TL. Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer. Br J Cancer. 2003;88:1301–9.

    Article  PubMed  CAS  Google Scholar 

  22. Kuss I, Donnenberg AD, Gooding W, Whiteside TL. Effector CD8+CD45RO-CD27-T cells have signalling defects in patients with squamous cell carcinoma of the head and neck. Br J Cancer. 2003;88:223–30.

    Article  PubMed  CAS  Google Scholar 

  23. Kim JW, Wieckowski E, Taylor DD, Reichert TE, Watkins S, Whiteside TL. Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes. Clin Cancer Res. 2005;11:1010–20.

    PubMed  CAS  Google Scholar 

  24. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91.

    Article  PubMed  CAS  Google Scholar 

  25. Bauernhofer T, Zenahlik S, Hofmann G, Balic M, Resel M, Pirchmoser R, Regitnig P, Ambros P, Dandachi N, Samonigg H. Association of disease progression and poor overall survival with detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer. Oncol Rep. 2005;13:179–84.

    PubMed  Google Scholar 

  26. Read S, Malmstrom V, Powrie F. Cytotoxic T . lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302.

    Article  PubMed  CAS  Google Scholar 

  27. Whiteside TL. Tumor-induced death of immune cells: its mechanisms and consequences. Semin Cancer Biol. 2002;12:43–50.

    Article  PubMed  CAS  Google Scholar 

  28. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med. 2001;194:823–32.

    Article  PubMed  CAS  Google Scholar 

  29. Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol. 2006;176:3321–9.

    PubMed  CAS  Google Scholar 

  30. Fritzsching B, Oberle N, Eberhardt N, Quick S, Haas J, Wildemann B, Krammer PH, Suri-Payer E. In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not . to TCR-mediated cell death. J Immunol. 2005;175:32–6.

    PubMed  CAS  Google Scholar 

  31. Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J, Krammer P, Linderkamp O, Suri-Payer E. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood. 2006;108:3371–8.

    Article  PubMed  CAS  Google Scholar 

  32. Bauernhofer T, Kuss I, Henderson B, Baum AS, Whiteside TL. Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. Eur J Immunol. 2003;33:119–24.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported in part by a research grant from Amgen GmbH, Austria.

Author information

Authors and Affiliations

  1. Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria

    Stefanie Stanzer, Nadia Dandachi, Marija Balic, Margit Resel, Hellmut Samonigg & Thomas Bauernhofer

Authors
  1. Stefanie Stanzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadia Dandachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marija Balic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margit Resel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hellmut Samonigg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Bauernhofer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefanie Stanzer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stanzer, S., Dandachi, N., Balic, M. et al. Resistance to Apoptosis and Expansion of Regulatory T Cells in Relation to the Detection of Circulating Tumor Cells in Patients with Metastatic Epithelial Cancer. J Clin Immunol 28, 107–114 (2008). https://doi.org/10.1007/s10875-007-9139-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-007-9139-2

Keywords

Search

Navigation