CD4(+)CD25(high) regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers

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(+)CD25(high) 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(+)CD25(high) 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(+)CD25(high) 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(+)CD25(high) 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(+)CD25(high) 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(+)CD25(high) 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(+)CD25(high) T cells individually increased compared to 2 months after the operations. CD4(+)CD25(high) 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(+)CD25(high) T regs.