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

ABSTRACT: Purpose: 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.Experimental Design: Patient-resected GBM, The Cancer Genome Atlas, human T-cell:GBM cocultures, as well as nu/nu, NOD-scid, and humanized (NSG-SGM3-BLT) mice-engrafted human GBM form the basis of our investigation.Results:In situ hybridization for IDO1 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 (P = 0.0076). GBM IDO1 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 IFN?-associated T-cell-mediated increase of intratumoral IDO1Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 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. Clin Cancer Res; 23(21); 6650-60. ©2017 AACR.

SUBMITTER: Zhai L

PROVIDER: S-EPMC5850948 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Zhai Lijie L Ladomersky Erik E Lauing Kristen L KL Wu Meijing M Genet Matthew M Gritsina Galina G Győrffy Balázs B Brastianos Priscilla K PK Binder David C DC Sosman Jeffrey A JA Giles Francis J FJ James Charles D CD Horbinski Craig C Stupp Roger R Wainwright Derek A DA

Clinical cancer research : an official journal of the American Association for Cancer Research 20170727 21

<b>Purpose:</b> 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 p ...[more]

PMID: 28751450

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Project description:BackgroundThe retinoblastoma (RB) transcriptional corepressor 1 protein functions to slow cell-cycle progression. Inactivation of RB by reduced expression and/or hyperphosphorylation allow for enhanced progression through the cell cycle. Murine models develop medullary thyroid carcinoma (MTC) after generalized loss of RB. However, RB expression in MTC has only been evaluated in a small number of tumors, with differing results. The objective of this study was to determine whether reduced expression of RB and/or overexpression of hyperphosphorylated RB predict MTC aggressive behavior.MethodsFormalin-fixed, paraffin-embedded primary thyroid tumors and lymph node metastases from MTC patients were evaluated for calcitonin, RB, and phosphorylated RB (pRB) expression by immunohistochemistry. Two expert pathologists evaluated the slides in a blinded manner, and the immunohistochemistry results were compared to disease-specific survival as a primary endpoint.ResultsSeventy-four MTC samples from 56 patients were analyzed in this study, including 51 primary tumors and 23?lymph node metastases. The median follow-up time was 6.75 years after surgery (range 0.64-24.30 years), and the median primary tumor size was 30?mm (range 6-96?mm). Sixty-six percent of cases were classified as stage IV. RB nuclear expression was diffusely present in 88% of primary tumors and 78% of lymph node metastases. Nuclear pRB expression was present in 22% of primary tumors and 22% of lymph node metastases. On univariate analysis, reduced RB (<75% tumor cell staining) trended with lower MTC-specific survival for primary tumor and metastatic nodes (primary tumor hazard ratio?=?3.54 [confidence interval 0.81-15.47], p?=?0.08; and lymph node hazard ratio?=?4.35 [confidence interval 0.87-21.83], p?=?0.05). For primary tumors, multivariable analysis showed that low nuclear RB expression was independently associated with worse disease-specific (p?=?0.01) and overall (p?=?0.02) survival. pRB levels were not associated with survival for either primary tumor or lymph node metastases.ConclusionsReduced RB expression is associated with decreased patient survival in univariate and multivariable analyses, independent from patient age at surgery or advanced TNM stage. Future studies involving larger MTC patient populations are warranted to determine if lower RB expression levels may serve as a biomarker for aggressive disease in patients with MTC.

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

Publications

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

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