Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival

• Published in: Clinical cancer research Vol. 23; no. 21; pp. 6650 - 6660
• Main Authors: Zhai, Lijie, Ladomersky, Erik, Lauing, Kristen L, Wu, Meijing, Genet, Matthew, Gritsina, Galina, Győrffy, Balázs, Brastianos, Priscilla K, Binder, David C, Sosman, Jeffrey A, Giles, Francis J, James, Charles D, Horbinski, Craig, Stupp, Roger, Wainwright, Derek A
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.11.2017
• Subjects: Adult; Adults; Aged; Aged, 80 and over; Animal models; Animals; Brain; Brain tumors; Cancer; Cell Line, Tumor; Coculture Techniques; Combinatorial analysis; Correlation; Dioxygenase; Disease-Free Survival; Experimental design; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Immunoregulation; Immunosuppression; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Male; Medical prognosis; Mice; Middle Aged; Multivariate statistical analysis; Prognosis; RNA, Messenger - genetics; Statistical analysis; Survival; Transcription; Xenograft Model Antitumor Assays; γ-Interferon
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-0120

Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome. Patient-resected GBM, The Cancer Genome Atlas, human T-cell:GBM cocultures, as well as nu/nu, NOD- and humanized (NSG-SGM3-BLT) mice-engrafted human GBM form the basis of our investigation. hybridization for revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis ( = 0.0076). GBM mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially engrafted human GBM revealed an IFNγ-associated T-cell-mediated increase of intratumoral Our data demonstrate that high intratumoral mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T-cell-mediated effects against GBM should consider combinatorial approaches that coinhibit potential T-cell-mediated IDO1 enhancement during therapy. .