Tumor‐Derived IDO Affects the Lifespan in a Mouse Model of Glioblastoma

Abstract

Glioblastoma multiforme (GBM) is a malignant brain tumor with an average survival time of one year. Our laboratory previously demonstrated that a subset of T cells, known as Tregs, infiltrate both human‐ and mouse models of‐GBM. Importantly, depleting Tregs leads to increased survival in a mouse model of GBM. Indoleamine 2,3 dioxygenase (IDO) has emerged as a molecule that controls Treg recruitment and/or activation and has recently been shown to be expressed in human GBM. Based on this association, we hypothesized that IDO is involved in GBM progression. Thus, this work set out to establish: 1) if IDO expression affected survival and, 2) where IDO is required to affect survival, in a mouse model of GBM. To determine if and where IDO is required to affect lifespan, we used wild‐type (WT) and IDO‐deficient (IDO−/−) mice, intracranial injections of the GBM‐like cell line, GL261, histological quantification of tumor size, immunofluorescence for IDO expression, small hairpin RNA knockdown for IDO, as well as mouse survival analysis. Here, we demonstrate that both WT and IDO−/− mice intracranially‐injected with GL261 cells and knocked‐down for IDO (GL261Kd) live significantly longer than WT and IDO−/− mice intracranially‐injected GL261 cells transduced with a scrambled control shRNA (GL261Vc) (p < 0.001). Histology confirms that the GL261Kd GBM grows significantly slower, when compared to the GL261Vc GBM (p < 0.001). This is co‐incident with a significant decrease in immunofluorescence for IDO expression in the GL261Kd‐, when compared to the GL261Vc‐GBM (p < 0.001). By using a pre‐clinical mouse model of GBM whereby IDO is deficient or knocked‐down in different anatomical compartments, this work demonstrates that IDO is an important molecule, required and sufficient for promoting brain tumor growth, supporting the future investigation of pharmacological inhibitors of IDO in patients with GBM.Grant Funding Source: 5R01CA138587‐03; 1F32NS073366‐ 01A1