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 co-cultures, 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 IFNg-associated T cell-mediated increase of intratumoral IDO1 . Conclusions: 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 co-inhibit potential T cell-mediated IDO1 enhancement during therapy.