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Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity¹

Yung-Chang Lin^*,, Li-Yuan Chang, Ching-Tai Huang^*,¶, Hui-Min Peng, Avijit Dutta^¶, Tse-Ching Chen^*,||, Chau-Ting Yeh^*, and Chun-Yen Lin^2,*,,

^* School of Medicine, College of Medicine, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Department of Hematology/Oncology, Department of Hepatogastroenterology, ^¶ Department of Infectious Disease, and ^|| Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

The phenomenon of concomitant tumor immunity involves a tumor-bearing host rejecting another similar tumor at a distant site and suggests the existence of tumor-specific immunity. Loss of this immunity may contribute to tumor metastasis. However, mechanisms underlying the loss of concomitant immunity are largely unknown. We set up a concomitant tumor immunity model in which this immunity is gradually lost as the primary tumor progresses. We found that CD8⁺ T cells, especially tumor-infiltrating CD8⁺ T cells, from mice that lost concomitant tumor immunity, possessed potent antitumor properties and strongly expressed effector molecules. Furthermore, effector/memory regulatory T cells (Treg cells, CD103⁺CD4⁺Foxp3⁺ T cells) increased as the primary tumor progressed. They initially accumulated around the tumor and in the spleen at later points. Not only did these cells more greatly express killing molecules, they also suppressed the functions of tumor-bearing CD8⁺ T cells in vitro and in vivo. Finally, we show that these effector/memory Treg cells inhibit concomitant tumor immunity in vivo. Taken together, data suggest that effector/memory Treg cells are responsible for the loss of concomitant tumor immunity associated with tumor progression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by NMRP Genome Projects 93-2314-B-182-023 and 95-2314-B-182-052 from the National Science Council, Taiwan, and by CMRPG 34033x, 361321, and 33007 from Chang Gung Memorial Hospital Medical Research Project Fund.

² Address correspondence and reprint requests to Dr. Chun-Yen Lin, Department of Hepatogastroenterology, Chang Gung Memorial Hospital, No. 5, Fushin Street, Kweishan, Taoyuan, 333 Taiwan. E-mail address: chunyenlin{at}gmail.com

³ Abbreviations used in this paper: Treg, regulatory T; TIL, tumor-infiltrating lymphocyte; GITR, glucocorticoid-induced TNFR; FasL, Fas ligand.