Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.
Tulane University Health Science Center, New Orleans, Louisiana 70112, USA.
Tyler J
TJ
Curiel
George
G
Coukos
Linhua
L
Zou
Xavier
X
Alvarez
Pui
P
Cheng
Peter
P
Mottram
Melina
M
Evdemon-Hogan
Jose R
JR
Conejo-Garcia
Lin
L
Zhang
Matthew
M
Burow
Yun
Y
Zhu
Shuang
S
Wei
Ilona
I
Kryczek
Ben
B
Daniel
Alan
A
Gordon
Leann
L
Myers
Andrew
A
Lackner
Mary L
ML
Disis
Keith L
KL
Knutson
Lieping
L
Chen
Weiping
W
Zou
D000818:Animals; D001201:Ascites / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D002465:Cell Movement / Q000276:immunology*; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D010051:Ovarian Neoplasms / Q000276:immunology*; D015375:Receptors, Interleukin-2; D013601:T-Lymphocytes / Q000276:immunology*
C515482:CCL22 protein, human; C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2