The immune tolerance of cancer is mediated by IDO that is inhibited by COX-2 inhibitors through regulatory T cells.
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.
Lee
Sung Yong
SY
Division of Respiratory and Critical Care, Department of Internal Medicine, Guro Hospital, Korea University, Seoul, Republic of Korea.
Choi
Hye Kyoung
HK
Lee
Kyoung Ju
KJ
Jung
Jin Yong
JY
Hur
Gyu Young
GY
Jung
Ki Hwan
KH
Kim
Je Hyeong
JH
Shin
Chol
C
Shim
Jae Jeong
JJ
In
Kwang Ho
KH
Kang
Kyung Ho
KH
Yoo
Se Hwa
SH
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
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