Is IDO1 an adequate target for treatment in glioblastoma?

Abstract

e14039 Background: Glioblastoma (GB) is the most prevalent primary brain tumor in adults. The first-line treatment is based on standard brain surgery and adjuvant radio-chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is a catabolic enzyme that plays a role in the metabolism of tryptophan (Trp), thereby promoting a state of immunosuppression. New treatments inhibiting this pathway are being tested in GB. This study aims to assess the expression of IDO in GB patients to determine whether this enzyme may be an actionable target for the treatment of GB. Methods: This is a retrospective transversal study whose database comes from the GLIOCAT project. Expression of IDO protein and mRNA was evaluated in tumor specimens of newly diagnosed GB patients by immunohistochemistry (IHC) (percentage of positive tumor cells) with an antibody anti-IDO1 (Sigma-Aldrich Cat#HPA027772) and by RNA sequencing (RNA-seq). RNA-seq (IIlumina HiSeq2000) in paired-end mode with a read length of 2x76bp using TruSeq SBS Kit v4). Reads were mapped to the human reference genome version hg38 with STAR. Genes were quantified with RSEM using gencode annotation version 24. Normalization of gene expression was performed with the trimmed-mean of M values (TMM) method. IDO gene expression values of -6 logCPM were considered as not expressed. Results: From the 255 samples assessed by IHC, 199 patients (78%) did not express IDO1 protein (mean 0.8±2.73, range 0-21%). From the 139 samples assessed by RNA-seq, TMM values, were negative for 49.6%, while low expression was detected for the other samples (mean -3.36 +/- 3.15 logCPM, range -6.12-4.32). Conclusions: Although IDO1 is barely expressed in normal brain tissue, certain studies show that its expression is upregulated in GB, either by tumor cells or indirectly induced in host antigen presenting cells, leading to immune evasion. Therefore, the metabolism of Trp is an attractive pathway to be targeted for the treatment of GB; however, our results show that IDO may not be the main target to be inhibited due to its undetectable or very low levels of expression.