Abstract A064: IDO1 expression stratifies glioblastoma patient survival and correlates with dominantly immunosuppressive pathways
Authors: Zhai Lijie , Genet Matthew , Ladomersky Erik , Lauing Kristen , Wu Meijing , Binder David , Kim Leo , Rich Jeremy , Horbinski Craig , James C. David , Sosman Jeffrey A. , Bloch Orin , Wainwright Derek A. 
Published: November 2016

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 &lt; 0.0001 in grade III; mean difference = 2.15, P &lt; 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 &lt; 0.0001), PD-L2 (r = 0.4871, P &lt; 0.0001), PD-1 (r = 0.3416, P &lt; 0.0001), CTLA-4 (r = 0.3534, P &lt; 0.0001), STAT3 (r = 0.2366, P = 0.0018), CD39 (r = 0.2691, P = 0.0004), BTLA (r = 0.2981, P &lt; 0.0001), Lag3 (r = 0.2567, P = 0.0007), FoxP3 (r = 0.1865, P &lt; 0.0143) and FGL2 (r = 0.4267, P &lt; 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.