title: Expression of indoleamine 2,3-dioxygenase and infiltration of FOXP3+ regulatory T cells are associated with aggressive features of papillary thyroid microcarcinoma.
abstract: BACKGROUND
  Indoleamine 2,3-dioxygenase (IDO) is overexpressed in many different types of tumor and is associated with activation of FOXP3+ regulatory T cells (Treg cells) and downregulation of cytotoxic cellular immunity in the tumor microenvironment. It has been suggested that IDO inhibitors can be utilized as an effective therapeutic agent against human cancers. However, the expression of IDO and its association with tumor-infiltrating lymphocytes (TILs) remain unclear in papillary thyroid microcarcinoma (PTMC).
  
  
  METHODS
  Immunohistochemical staining for IDO expression was performed on 124 PTMC samples. TIL subsets (CD3+, CD8+, and FOXP3+ T cells) were counted in serial sections. The relationships between the expression of IDO and infiltration of TIL subsets, as well as the relationships between these immunomodulating factors and clinicopathologic parameters of PTMCs, were analyzed.
  
  
  RESULTS
  There was a significant correlation between IDO expression and reduced CD3+ TIL and increased FOXP3+ TIL. IDO expression was found in 31% of PTMC and was associated with aggressive clinicopathologic features of the tumor such as extrathyroidal extension (ETE) and multifocality. High infiltration of FOXP3+ Treg cells in the tumor was associated with lymph node metastasis, ETE, and multifocality. Furthermore, high FOXP3/CD8+ ratio was associated with multifocality and lymph node metastasis, and high FOXP3+/CD3+ ratio was related to ETE and multifocality. In multivariate analyses, IDO expression was found to be an independent predictive factor for ETE and tumor multifocality.
  
  
  CONCLUSIONS
  IDO expression and infiltration of FOXP3+ Treg cells were closely related to each other and were associated with aggressive features of PTMC, suggesting that disruption of antitumor immunity by IDO expression, and thus, infiltration of FOXP3+ Treg cells may contribute to tumor progression in PTMC.
authors.affiliation: 1 Department of Pathology, Seoul National University Hospital , Seoul, South Korea .
authors.forename: Han Suk
authors.initials: HS
authors.lastname: Ryu
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Park
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Yul Ri
authors.initials: YR
authors.lastname: Chung
authors.forename: Cha Kyong
authors.initials: CK
authors.lastname: Yom
authors.forename: Soon-Hyun
authors.initials: SH
authors.lastname: Ahn
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Park
authors.forename: Seong Hoe
authors.initials: SH
authors.lastname: Park
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002291:Carcinoma, Papillary / Q000201:enzymology*; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology*; D013964:Thyroid Neoplasms / Q000201:enzymology*; D013967:Thyroiditis, Autoimmune / Q000503:physiopathology
chemical_list: D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf