Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-Hodgkin lymphoma correlates with increased regulatory T-cell infiltration

Leuk Lymphoma. 2014 Feb;55(2):405-14. doi: 10.3109/10428194.2013.804917. Epub 2013 Jun 26.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), which is a key enzyme in tryptophan metabolism expressed in some subsets of normal and neoplastic cells, participates in tumor-induced tolerance. However, the mechanisms involved are not clearly understood. A hypothesis suggests that IDO1 may be involved in proliferation and conversion of regulatory T cells (Tregs). In this study, we evaluated the levels of IDO1 and forkhead box P3 (FoxP3) in non-Hodgkin lymphoma (NHL) tissues and performed ex vivo experiments to investigate the role of IDO1 on T-cell tolerance in NHL. The results showed that expressions of IDO1 mRNA and protein were coincidentally higher in NHL tissues than in reactive hyperplasia of lymph node tissues. Up-regulation of IDO1 was correlated with later clinical phases, larger tumors and higher serum lactate dehydrogenase (LDH), and indicated a worse prognosis. FoxP3 mRNA and protein levels were markedly increased alongside elevated IDO1 levels. Co-culture of murine CD4 + CD25- T cells with A20 cells could initiate the conversion of CD4 + CD25+ T cells, which showed a suppressive function in the mixed lymphocyte reaction. Moreover, the potent inhibitor of IDO1, 1-methyl-l-tryptophan, attenuated the conversion of CD4 + CD25- T cells into CD4 + CD25+ FoxP3 + T cells. The results suggested that up-regulation of IDO1 in NHL tissues could induce local immune tolerance by favoring development and infiltration of FoxP3 + Tregs through the conversion of CD4 + CD25- T cells into CD4 + CD25+ FoxP3 + T cells in the tumor microenvironment. This could be a novel mechanism of NHL escape from immune control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Coculture Techniques
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Kaplan-Meier Estimate
  • Lymphoma, Non-Hodgkin / genetics*
  • Lymphoma, Non-Hodgkin / metabolism
  • Lymphoma, Non-Hodgkin / pathology
  • Male
  • Mice
  • Middle Aged
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • Tryptophan / analogs & derivatives
  • Tryptophan / pharmacology
  • Up-Regulation*
  • Young Adult

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-2 Receptor alpha Subunit
  • indoleamine 2,3-dioxygenase 1, human
  • Tryptophan
  • 1-methyltryptophan