title: Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection.
abstract: BACKGROUND
  The mechanism by which pancreatic ductal adenocarcinoma (PDA) cells escape immune detection and survive in lymph nodes is poorly understood. One possible mechanism by which PDA cells can escape immune detection is through upregulation of indoleamine 2,3-dioxygenase (IDO), an enzyme that can starve T lymphocytes of tryptophan.
  
  
  METHODS
  Seventeen cases of PDA were evaluated by immunohistochemistry for expression of IDO in tumor cells and the number of Forkhead box p3-expressing regulatory T cells. To validate IDO protein expression, Western blot analysis for IDO was performed on primary pancreatic cancer cell-line protein lysates.
  
  
  RESULTS
  Upregulation of IDO in metastatic PDA cells was associated with an increased number of regulatory T cells. Cytoplasmic IDO expression was present in all tumors (primary and metastatic) from patients with lymph node metastases. Intensity of staining was stronger in the corresponding metastatic foci when compared with the primary tumor. Three nonmetastatic PDAs were negative or only focally positive for IDO. Additionally, IDO expression in PDA was independent of tumor histologic grade. Forkhead box p3 regulatory T cells were increased in lymph nodes containing metastatic tumor cells expressing IDO. Using Western blot and reverse transcriptase polymerase chain reaction analysis, we validated that IDO expression in pancreatic cancer cells is induced by interferon-gamma as reported previously.
  
  
  CONCLUSIONS
  These data support the notion that metastatic PDA cells select for overexpression of IDO to evade immunologic detection. Future studies will define whether IDO expression in PDA patients with lymph node-positive metastases correlates with decreased survival. In addition, inhibition of IDO in PDA patients can be useful to enhance immunotherapeutic strategies.
authors.affiliation: Department of Pathology, Jefferson Center for Pancreatic, Biliary and Related Cancers, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Witkiewicz
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Williams
authors.forename: Joseph
authors.initials: J
authors.lastname: Cozzitorto
authors.forename: Brandice
authors.initials: B
authors.lastname: Durkan
authors.forename: Shayna L
authors.initials: SL
authors.lastname: Showalter
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000556:secondary; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000276:immunology*; D008198:Lymph Nodes / Q000737:chemistry / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase