The immune tolerance of cancer is mediated by IDO that is inhibited by COX-2 inhibitors through regulatory T cells

Sung Yong Lee, Hye Kyoung Choi, Kyoung Ju Lee, Jin Yong Jung, Gyu Young Hur, Ki Hwan Jung, Je Hyeong Kim, Chol Shin, Jae Jeong Shim, Kwang Ho In, Kyung Ho Kang, Se Hwa Yoo

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)22-28
Number of pages7
JournalJournal of Immunotherapy
Volume32
Issue number1
DOIs
Publication statusPublished - 2009 Jan

Keywords

  • COX-2
  • Foxp3
  • IDO
  • Immune tolerance
  • PGE2
  • Regulatory T cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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