title: The immune tolerance of cancer is mediated by IDO that is inhibited by COX-2 inhibitors through regulatory T cells.
abstract: Prostaglandin (PGE2), synthesized by cyclooxygenase-2 (COX-2), is associated with cellular immune tolerance during the process of cancer development. Induction of tolerance requires a specific environment in which dendritic cells and regulatory T cells (Tregs) play an essential role. It was recently shown that maturation of dendritic cells in the presence of indoleamine 2, 3-dioxygenase (IDO) results in activation of Tregs, and inhibition of COX-2 activity regulated IDO expression within the tumor microenvironment. Thus, we hypothesized that the tumor immune tolerance would be inhibited by COX-2 inhibitor and this inhibition would be mediated by IDO-dependent Tregs inhibition. The PGE2 in Lewis lung cancer cells (3LL) and serum of mice were measured for the evaluation of COX-2 inhibitors' local and systemic effects. The production of PGE2 in 3LL cells and serum of 3LL tumor-bearing mice were decreased by COX-2 inhibition. However, there were no significant differences in serum PGE2 levels among normal control and celecoxib-treated nontumor-bearing mice. The accumulation of Tregs was reduced in the celecoxib-treated 3LL tumor-bearing mice. In addition, the expressions of COX-2, IDO, and Foxp3 were reduced in the mice treated with a COX-2 inhibitor, and this was found to correlate with a reduction in the size of tumor mass and metastasis. These results suggest that the antitumor effects of COX-2 inhibitors seemed to be correlated with the inhibition of IDO and Tregs. Therefore, COX-2 inhibitors might provide a therapeutic strategy for Tregs-induced tumor immune tolerance.
authors.affiliation: Division of Respiratory and Critical Care, Department of Internal Medicine, Guro Hospital, Korea University, Seoul, Republic of Korea.
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Hye Kyoung
authors.initials: HK
authors.lastname: Choi
authors.forename: Kyoung Ju
authors.initials: KJ
authors.lastname: Lee
authors.forename: Jin Yong
authors.initials: JY
authors.lastname: Jung
authors.forename: Gyu Young
authors.initials: GY
authors.lastname: Hur
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Jung
authors.forename: Je Hyeong
authors.initials: JH
authors.lastname: Kim
authors.forename: Chol
authors.initials: C
authors.lastname: Shin
authors.forename: Jae Jeong
authors.initials: JJ
authors.lastname: Shim
authors.forename: Kwang Ho
authors.initials: KH
authors.lastname: In
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Kang
authors.forename: Se Hwa
authors.initials: SH
authors.lastname: Yoo
mesh_terms: D000818:Animals; D000068579:Celecoxib; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D015232:Dinoprostone