title: Indoleamine 2,3-dioxygenase 1 (IDO1) is up-regulated in thyroid carcinoma and drives the development of an immunosuppressant tumor microenvironment.
abstract: BACKGROUND
  Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it appears to exert an immunosuppressive function as part of an acquired mechanism of immune escape mediated by the inhibition of lymphocyte proliferation and survival and by the induction of FoxP3+ T regulatory cells.
  
  
  OBJECTIVE
  The objective of the study was to evaluate IDO1 expression in thyroid carcinoma and demonstrate its immunosuppressive function in the context of thyroid tumors.
  
  
  METHODS
  IDO1 expression was evaluated by quantitative PCR in 105 papillary thyroid carcinomas (PTCs), 11 medullary thyroid carcinomas, six anaplastic thyroid carcinomas, and five thyroid carcinoma cell lines (TCCLs), by immunohistochemistry in 55 PTCs and by Western blotting in five TCCLs. FoxP3+ Treg lymphocyte density was evaluated by immunohistochemistry in 29 PTCs. IDO1 inhibitory effect on lymphocyte proliferation was tested in coculture experiments of TCCLs and activated lymphocytes.
  
  
  RESULTS
  IDO1 mRNA expression resulted significantly higher in all the analyzed thyroid carcinoma histotypes compared with normal thyroid. Interestingly, an increase of IDO1 mRNA expression magnitude could be observed with gain of aggressiveness (PTCs and medullary thyroid carcinomas ≪ anaplastic thyroid carcinomas). In PTCs, IDO1 mRNA expression magnitude correlated with IDO1 immunostaining intensity in cancer cells and with FoxP3+ Treg lymphocyte density in the tumor microenvironment. IDO1 was expressed in human thyroid cancer cell lines in vitro, and FTC-133 cells showed high kynurenine concentration in the conditioned medium and a strong suppressive action on the proliferation of activated lymphocytes in coculture experiments.
  
  
  CONCLUSIONS
  For the first time, this study demonstrates a pivotal role of IDO1 in the suppression of lymphocyte function in thyroid carcinoma microenvironment.
authors: Departments of Internal Medicine (S.Moret., E.M., P.V., S.Morel., S.C., V.B., E.P.), Experimental Medicine and Biochemical Sciences (R.C., F.F., C.O., M.G.M., P.P.), Clinical and Experimental Medicine (A.A., R.G.), Chemistry and Drug Technology (A.M.), and Surgery (N.A.), University of Perugia, 06132 Perugia, Italy; Research Centre of Thyroid Proteomics and Genomics (S.Moret., E.M., P.V., S.Morel., N.A., E.P.), University of Perugia, 05100 Terni, Italy; Department of Clinical Sciences (M.S., S.F.), University of Rome "Sapienza," 00161 Rome, Italy; Department of Medicine (D.d.B., G.T.), Anatomic Pathology Unit, Bellaria Hospital, University of Bologna, 40139 Bologna, Italy; and Department of Molecular Medicine and Biotechnological Sciences (R.M.M., M.S.), University of Naples "Federico II," 80138 Naples, Italy.
authors: Sonia
authors: S
authors: Moretti
authors: Elisa
authors: E
authors: Menicali
authors: Pasquale
authors: P
authors: Voce
authors: Silvia
authors: S
authors: Morelli
authors: Sara
authors: S
authors: Cantarelli
authors: Marialuisa
authors: M
authors: Sponziello
authors: Renato
authors: R
authors: Colella
authors: Francesca
authors: F
authors: Fallarino
authors: Ciriana
authors: C
authors: Orabona
authors: Alessia
authors: A
authors: Alunno
authors: Dario
authors: D
authors: de Biase
authors: Vittorio
authors: V
authors: Bini
authors: Maria Grazia
authors: MG
authors: Mameli
authors: Sebastiano
authors: S
authors: Filetti
authors: Roberto
authors: R
authors: Gerli
authors: Antonio
authors: A
authors: Macchiarulo
authors: Rosa Marina
authors: RM
authors: Melillo
authors: Giovanni
authors: G
authors: Tallini
authors: Massimo
authors: M
authors: Santoro
authors: Paolo
authors: P
authors: Puccetti
authors: Nicola
authors: N
authors: Avenia
authors: Efisio
authors: E
authors: Puxeddu
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018276:Carcinoma, Medullary / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger