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Abstract A064: IDO1 expression stratifies glioblastoma patient survival and correlates with dominantly immunosuppressive pathways

Lijie Zhai, Matthew Genet, Erik Ladomersky, Kristen Lauing, Meijing Wu, David Binder, Leo Kim, Jeremy Rich, Craig Horbinski, C. David James, Jeffrey A. Sosman, Orin Bloch and Derek A. Wainwright
Lijie Zhai
1Department of Neurological Surgery, Northwestern University, Chicago, IL;
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Matthew Genet
1Department of Neurological Surgery, Northwestern University, Chicago, IL;
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Erik Ladomersky
1Department of Neurological Surgery, Northwestern University, Chicago, IL;
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Kristen Lauing
1Department of Neurological Surgery, Northwestern University, Chicago, IL;
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Meijing Wu
1Department of Neurological Surgery, Northwestern University, Chicago, IL;
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David Binder
2Department of Pathology, University of Chicago, Chicago, IL;
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Leo Kim
3Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH;
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Jeremy Rich
3Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH;
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Craig Horbinski
4Department of Neurological Surgery, Department of Pathology, Northwestern University, Chicago, IL;
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C. David James
5Department of Neurological Surgery, Department of Biochemistry and Molecular Genetics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL;
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Jeffrey A. Sosman
6Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL;
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Orin Bloch
7Department of Neurological Surgery, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL;
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Derek A. Wainwright
8Department of Neurological Surgery, Department of Microbiology-Immunology, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL.
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DOI: 10.1158/2326-6066.IMM2016-A064 Published November 2016
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Abstracts: Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; September 25-28, 2016; New York, NY

Abstract

Purpose: The objective of this study was to evaluate the prognostic significance of the immunosuppressive molecule indoleamine 2, 3-dioxygenase (IDO1) mRNA expression in patients with low-grade glioma (LGG) and glioblastoma (GBM).

Experimental Design: Hi-RNA-seq. Illumina data mined from the cancer genome atlas (TCGA) reflecting 475 LGG (WHO grade II and III) and 172 GBM patients were utilized to characterize the pattern of IDO1 mRNA expression. Kaplan-Meier (KM) survival analysis and multivariate Cox proportional hazards regression were conducted to evaluate the significance of IDO1 expression as a stratification marker in glioma patients. mRNA expression of proinflammatory and immunosuppressive factor genes were also investigated for their correlation with IDO1 mRNA expression. Ivy GAP analysis was further utilized to localize IDO1 mRNA within different GBM anatomic niches.

Results: Expression profiling of the TCGA revealed a distinct pattern of progressively increasing IDO1 mRNA levels correlating with decreased survival both in LGG and GBM patients. In grade III LGG and GBM, IDO1 mRNA expression was significantly decreased when mutant isocitrate dehydrogenase 1 and 2 (mIDH1/2) was coincidently expressed when compared to samples with wild-type IDH1/2 expression (mean difference = 1.51, P < 0.0001 in grade III; mean difference = 2.15, P < 0.01 in GBM). KM analysis and multivariate Cox regression analysis found IDO1 mRNA expression levels to be an independent prognostic factor for survival among LGG (P = 0.0115; HR = 1.68) and GBM (P = 0.0076; HR = 1.82) patients. Pearson's correlation analysis identified significant associations among GBM between IDO1 and the genes encoding immunosuppressive factors including PD-L1 (r = 0.2993, P < 0.0001), PD-L2 (r = 0.4871, P < 0.0001), PD-1 (r = 0.3416, P < 0.0001), CTLA-4 (r = 0.3534, P < 0.0001), STAT3 (r = 0.2366, P = 0.0018), CD39 (r = 0.2691, P = 0.0004), BTLA (r = 0.2981, P < 0.0001), Lag3 (r = 0.2567, P = 0.0007), FoxP3 (r = 0.1865, P < 0.0143) and FGL2 (r = 0.4267, P < 0.0001). Notably, IDO1 mRNA levels were higher in the cellular (1.398 ± 0.1257, mean ± SEM) and necrotic (1.543 ± 0.1489) GBM zones, when compared to infiltrating (0.9303 ± 0.0786) and leading margins (0.9064 ± 0.1224). Additionally, for the IDO1 paralog genes IDO2 and TDO2, which encodes indoleamine 2, 3-dioxygenase 2 and tryptophan dioxygenase respectively, no overall differential expression pattern were observed between different pathological grades nor a significant stratification in LGG and GBM patient survival.

Conclusions: Our data show for the first time that IDO1 mRNA levels can be used as an independent prognostic variable for patients with LGG and/or GBM. Given that ongoing IDO1-targeted immunotherapy clinical trials aim to inhibit enzymatic activity in malignant glioma, our data suggest that targeted subject enrollment may result in a better clinical response to therapy.

Citation Format: Lijie Zhai, Matthew Genet, Erik Ladomersky, Kristen Lauing, Meijing Wu, David Binder, Leo Kim, Jeremy Rich, Craig Horbinski, C. David James, Jeffrey A. Sosman, Orin Bloch, Derek A. Wainwright. IDO1 expression stratifies glioblastoma patient survival and correlates with dominantly immunosuppressive pathways [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A064.

  • ©2016 American Association for Cancer Research.
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Cancer Immunology Research: 4 (11 Supplement)
November 2016
Volume 4, Issue 11 Supplement
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Abstract A064: IDO1 expression stratifies glioblastoma patient survival and correlates with dominantly immunosuppressive pathways
Lijie Zhai, Matthew Genet, Erik Ladomersky, Kristen Lauing, Meijing Wu, David Binder, Leo Kim, Jeremy Rich, Craig Horbinski, C. David James, Jeffrey A. Sosman, Orin Bloch and Derek A. Wainwright
Cancer Immunol Res November 1 2016 (4) (11 Supplement) A064; DOI: 10.1158/2326-6066.IMM2016-A064

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Abstract A064: IDO1 expression stratifies glioblastoma patient survival and correlates with dominantly immunosuppressive pathways
Lijie Zhai, Matthew Genet, Erik Ladomersky, Kristen Lauing, Meijing Wu, David Binder, Leo Kim, Jeremy Rich, Craig Horbinski, C. David James, Jeffrey A. Sosman, Orin Bloch and Derek A. Wainwright
Cancer Immunol Res November 1 2016 (4) (11 Supplement) A064; DOI: 10.1158/2326-6066.IMM2016-A064
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  • Abstract B200: Single-cell RNA-sequencing (ScRNA-seq) reveals broad heterogeneity among CD8 T-cells during chronic viral infection and identifies a critical role for CD4 help in promoting the differentiation of a potent cytotoxic CD8 T-cell subset
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Show more Other Topics: Poster Presentations - Proffered Abstracts
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