title: Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-Hodgkin lymphoma correlates with increased regulatory T-cell infiltration.
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.
authors.affiliation: Department of Hematology, Provincial Hospital Affiliated to Shandong University , Jinan, Shandong , P. R. China.
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Liu
authors.forename: Kang
authors.initials: K
authors.lastname: Lu
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Feng
authors.forename: Mei
authors.initials: M
authors.lastname: Ding
authors.forename: Jun-Ming
authors.initials: JM
authors.lastname: Gao
authors.forename: Xue-Ling
authors.initials: XL
authors.lastname: Ge
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D014364:Tryptophan; C525396:1-methyltryptophan