IDO Expression in Brain Tumors Increases the Recruitment of Regulatory T Cells and Negatively Impacts Survival

• Published in: Clinical cancer research Vol. 18; no. 22; pp. 6110 - 6121
• Main Authors: WAINWRIGHT, Derek A, BALYASNIKOVA, Irina V, CHANG, Alan L, AHMED, Atique U, MOON, Kyung-Sub, AUFFINGER, Brenda, TOBIAS, Alex L, YU HAN, LESNIAK, Maciej S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.11.2012
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Brain Neoplasms - enzymology; Brain Neoplasms - immunology; Brain Neoplasms - mortality; Cell Line, Tumor; Gene Expression; Gene Knockdown Techniques; Glioblastoma - enzymology; Glioblastoma - immunology; Glioblastoma - mortality; Glucocorticoid-Induced TNFR-Related Protein - genetics; Glucocorticoid-Induced TNFR-Related Protein - metabolism; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Kaplan-Meier Estimate; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Transplantation; Neurology; Pharmacology. Drug treatments; Prognosis; RNA, Small Interfering - genetics; T-Lymphocytes, Regulatory - immunology; Tumors of the nervous system. Phacomatoses; Up-Regulation; Intracranial; Nervous system diseases; Enzyme; Treg cell; Gene expression; Survival; Intracranial tumor; Cerebral disorder; Recruitment; Central nervous system disease; T-Lymphocyte; Indoleamine-pyrrole 2,3-dioxygenase; Oxidoreductases; Regulatory cell
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-2130

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. 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. 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. 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.