CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers.
OBJECTIVE
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.
Kono
Koji
K
First Department of Surgery, University of Yamanashi, 1110 Shimokato, Tamaho, 409-3898 Yamanashi, Japan. kojikono@yamanashi.ac.jp
Kawaida
Hiromichi
H
Takahashi
Akihiro
A
Sugai
Hidemitsu
H
Mimura
Kosaku
K
Miyagawa
Naoto
N
Omata
Hideo
H
Fujii
Hideki
H
D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000276:immunology* / Q000401:mortality; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000276:immunology* / Q000401:mortality; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015375:Receptors, Interleukin-2