Skip to main content

Advertisement

Log in

CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers

Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose: Regulatory T cells (T regs) can inhibit immune responses mediated by T cells. It has been shown that there is an increased proportion of T regs in several different human malignancies, although the actual mechanism remains unclear. In the present study, we evaluated the prevalence of CD4(+)CD25high T regs in PBMCs from patients with gastric and esophageal cancers in relation to the clinical outcome. Methods: PBMCs in 72 patients with gastric cancer and 42 patients with esophageal cancer were evaluated for the proportion of CD4(+)CD25high T cells, as a percentage of the total CD4(+) cells, by flow cytometric analysis with triple-color staining. Actuarial overall survival rates of the patients were analyzed by the Kaplan–Meier method. Results: The percentages of CD4(+)CD25high T cells for cases of gastric cancer (4.9±1.2%) and esophageal cancer (5.2±2.1%) were significantly higher than those for healthy donors (1.9±1.1%, P<0.01). There were significant differences in the prevalence of CD4(+)CD25high T cells between the early and advanced disease stages, both in gastric cancer (stage I vs. III, P<0.05; stage I vs. IV, P<0.05) and esophageal cancer (stage I vs. IV, P<0.05). The patients with a high proportion of CD4(+)CD25high T cells showed poorer survival rates in comparison to those with a low proportion, in both gastric and esophageal cancers. After patients received curative resections of gastric cancers (n=57), the increased proportions of CD4(+)CD25high T cells were significantly reduced, and the levels were almost equal to those in normal healthy donors. In addition, studies of gastric cancer patients with postoperative recurrent tumors (n=6) revealed that the prevalence of CD4(+)CD25high T cells individually increased compared to 2 months after the operations. CD4(+)CD25high T cells expressed FOXP3 mRNA and had abundant CD45RO and intracellular CTLA-4 molecules. Conclusions: These results strongly suggest that tumor-related factors induce and expand CD4(+)CD25high T regs.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Joneleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH (2001) Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 193:1285–1294

    Article  PubMed  Google Scholar 

  2. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards A, Issacs J, Lechler RI (2001) Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood 98:2736–2744

    Article  PubMed  CAS  Google Scholar 

  3. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164

    PubMed  CAS  Google Scholar 

  4. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193:1303–1310

    Article  PubMed  CAS  Google Scholar 

  5. Asano M, Toda M, Sakaguchi N, Sakaguchi S (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184:387–396

    Article  PubMed  CAS  Google Scholar 

  6. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32

    Article  PubMed  CAS  Google Scholar 

  7. Weiner HL (2001) Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 182:207–214

    Article  PubMed  CAS  Google Scholar 

  8. Groux H, O’Garra A, Bigler M (1997) A CD4+T cells subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742

    Article  PubMed  CAS  Google Scholar 

  9. Thomason AM, Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287–296

    Article  PubMed  Google Scholar 

  10. Thomason AM, Shevach EM (2000) Suppressor effector function of CD4+25+immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190

    PubMed  Google Scholar 

  11. Takahashi T, Tagami T, Yamazaki S, Ueda T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310

    Article  PubMed  CAS  Google Scholar 

  12. Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458

    Article  PubMed  CAS  Google Scholar 

  13. Shevach EM (2001) Certified professionals: CD4+CD25+ suppressor T cells. J Exp Med 193:F41–F46

    Article  PubMed  CAS  Google Scholar 

  14. Azuma T, Takahashi T, Kinusato A, Kitamura T, Hirai H (2003) Human CD4+25+ regulatory T cells suppress NKT cells functions. Cancer Res 63:4516–4520

    PubMed  CAS  Google Scholar 

  15. Baecher-Allan C, Viglietta V, Hafler DA (2004) Human CD4+CD25+ regulatory T cells. Semin Immunol 26:89–97

    Article  Google Scholar 

  16. Baecher-Allan C, Viglietta V, Hafler DA (2002) Inhibition of human CD4(+)CD25(+high) regulatory T cell function. J Immunol 169:6210–6217

    PubMed  CAS  Google Scholar 

  17. Baecher-Allan C, Wolf E, Hafler DA (2005) Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+ CD25+ T cells. Clin Immunol 115:10–8

    Article  PubMed  CAS  Google Scholar 

  18. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H (2003) Increased populations of regulatory T cells in peripheral blood and tumo-infiltrating lymphocytes in patient with gastric and esophageal cancers. Clin Cancer Res 9:4404–4408

    PubMed  Google Scholar 

  19. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606–612

    PubMed  Google Scholar 

  20. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A (2003) CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98:1089–1099

    Article  PubMed  Google Scholar 

  21. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761

    PubMed  CAS  Google Scholar 

  22. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH (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 61:4766–4773

    PubMed  CAS  Google Scholar 

  23. Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, Kaiser LR, June CH (2002) Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168:4272–4276

    PubMed  CAS  Google Scholar 

  24. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  PubMed  CAS  Google Scholar 

  25. Kawaida H, Kono K, Takahashi A, Sugai A, Mimura K, Miyagawa N, Omata H, Kumamoto H, Ooi A, Fujii H (2005) Distribution of regulatory T cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res 124:151–157

    Article  PubMed  CAS  Google Scholar 

  26. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+CD25 high regulatory cells in human peripheral blood. J Immunol 167:1245–1253

    PubMed  CAS  Google Scholar 

  27. Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC, Roncarolo MG (2002) Human CD25+CD4+ T suppressor cell clones produce transforming growth factor beta, but not interleukin 10, and are distinct from type 1 T regulatory cells. J Exp Med 196:1335–1346

    Article  PubMed  CAS  Google Scholar 

  28. Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto Y (2002) Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res 8:1767–1771

    PubMed  CAS  Google Scholar 

  29. Kono K, Takahashi A, Sugai H, Fujii H, Choudhury AR, Kiessling R, Matsumoto Y (2002) Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T cell responses in patients with gastric cancer. Clin Cancer Res 8:3394–3400

    PubMed  CAS  Google Scholar 

  30. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ (2001) 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 194:823–832

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Koji Kono.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kono, K., Kawaida, H., Takahashi, A. et al. CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 55, 1064–1071 (2006). https://doi.org/10.1007/s00262-005-0092-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-005-0092-8

Keywords

Navigation