title: IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival.
abstract: OBJECTIVE
  Glioblastoma multiforme (GBM) is an aggressive adult brain tumor with a poor prognosis. One hallmark of GBM is the accumulation of immunosuppressive and tumor-promoting CD4(+)FoxP3(+)GITR(+) regulatory T cells (Tregs). Here, we investigated the role of indoleamine 2,3 dioxygenase (IDO) in brain tumors and the impact on Treg recruitment.
  
  
  METHODS
  To determine the clinical relevance of IDO expression in brain tumors, we first correlated patient survival to the level of IDO expression from resected glioma specimens. We also used novel orthotopic and transgenic models of glioma to study how IDO affects Tregs. The impact of tumor-derived and peripheral IDO expression on Treg recruitment, GITR expression, and long-term survival was determined.
  
  
  RESULTS
  Downregulated IDO expression in glioma predicted a significantly better prognosis in patients. Coincidently, both IDO-competent and deficient mice showed a survival advantage bearing IDO-deficient brain tumors, when compared with IDO-competent brain tumors. Moreover, IDO deficiency was associated with a significant decrease in brain-resident Tregs, both in orthotopic and transgenic mouse glioma models. IDO deficiency was also associated with lower GITR expression levels on Tregs. Interestingly, the long-term survival advantage conferred by IDO deficiency was lost in T-cell-deficient mice.
  
  
  CONCLUSIONS
  These clinical and preclinical data confirm that IDO expression increases the recruitment of immunosuppressive Tregs that lead to tumor outgrowth. In contrast, IDO deficiency decreases Treg recruitment and enhances T-cell-mediated tumor rejection. Thus, the data suggest a critical role for IDO-mediated immunosuppression in glioma and support the continued investigation of IDO-Treg interactions in the context of brain tumors.
authors.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Wainwright
authors.forename: Irina V
authors.initials: IV
authors.lastname: Balyasnikova
authors.forename: Alan L
authors.initials: AL
authors.lastname: Chang
authors.forename: Atique U
authors.initials: AU
authors.lastname: Ahmed
authors.forename: Kyung-Sub
authors.initials: KS
authors.lastname: Moon
authors.forename: Brenda
authors.initials: B
authors.lastname: Auffinger
authors.forename: Alex L
authors.initials: AL
authors.lastname: Tobias
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000401:mortality; D045744:Cell Line, Tumor; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000201:enzymology* / Q000276:immunology / Q000401:mortality; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D034741:RNA, Small Interfering; C491405:TNFRSF18 protein, human