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

Cancer Immunol Immunother. 2006 Sep;55(9):1064-71. doi: 10.1007/s00262-005-0092-8. Epub 2005 Nov 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Disease Progression
  • Esophageal Neoplasms / immunology*
  • Esophageal Neoplasms / mortality
  • Female
  • Humans
  • Immunophenotyping
  • Leukocytes, Mononuclear / immunology
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Receptors, Interleukin-2 / biosynthesis*
  • Stomach Neoplasms / immunology*
  • Stomach Neoplasms / mortality
  • Survival Rate
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / immunology*


  • Receptors, Interleukin-2