Increased tumor-infiltrating CD8(+)Foxp3(+) T lymphocytes are associated with tumor progression in human gastric cancer.
BACKGROUND
CD8(+)Foxp3(+) T lymphocytes have been detected in tumors. However, the distribution, phenotypic features, and regulation of these cells in gastric cancer remain unknown.


METHODS
The levels of CD8(+)Foxp3(+) T lymphocytes in the peripheral blood, tumor-draining lymph nodes, non-tumor tissues, and tumor tissues of patients with gastric cancer were detected by flow cytometry. Foxp3 induction in CD8(+)Foxp3(-) T cells was investigated in vitro. The suppressive function of CD8(+)Foxp3(+) T lymphocytes was analyzed by their effect on CD4(+) T-cell proliferation and IFN-γ production. The percentages of CD8(+)Foxp3(+) T lymphocytes were evaluated for the association with tumor stage.


RESULTS
The frequency of CD8(+)Foxp3(+) T lymphocytes in tumor tissues was significantly higher than that in non-tumor tissues, and similar results were also observed in tumor-draining lymph nodes compared with peripheral blood. Most intratumoral CD8(+)Foxp3(+) T lymphocytes were activated effector cells (CD45RA(-)CD27(-)). TGF-β1 levels were positively correlated with the frequency of CD8(+)Foxp3(+) T lymphocytes in tumor tissues, and in vitro TGF-β1 could induce the generation of CD8(+)Foxp3(+) T lymphocytes in a dose-dependent manner. Furthermore, intratumoral CD8(+)Foxp3(+) T lymphocytes suppressed the proliferation and IFN-γ production of CD4(+) T cells. Finally, intratumoral CD8(+)Foxp3(+) T lymphocytes were significantly increased with tumor progression in terms of tumor-node-metastasis (TNM) stage.


CONCLUSIONS
Our data have shown that increased intratumoral CD8(+)Foxp3(+) T lymphocytes are associated with tumor stage and potentially influence CD4(+) T-cell functions, which may provide insights for developing novel immunotherapy protocols against gastric cancer.
Department of Clinical Microbiology and Immunology, College of Medical Laboratory Science, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing 400038, People's Republic of China.
Liu-Sheng
LS
Peng
Yuan
Y
Zhuang
Yun
Y
Shi
Yong-Liang
YL
Zhao
Ting-Ting
TT
Wang
Na
N
Chen
Ping
P
Cheng
Tao
T
Liu
Xiao-Fei
XF
Liu
Jin-Yu
JY
Zhang
Qian-Fei
QF
Zuo
Xu-Hu
XH
Mao
Gang
G
Guo
Dong-Shui
DS
Lu
Pei-Wu
PW
Yu
Quan-Ming
QM
Zou
D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000494:pharmacology
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma