Tumor cell IDO enhances immune suppression and decreases survival independent of tryptophan metabolism in glioblastoma

Purpose Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to-date. Greater than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that requires intratumoral Trp depletion. However, recent findings led us to investigate the alternative hypothesis that IDO suppresses the anti-GBM immune response independent of its association with Trp metabolism. Experimental design IDO-deficient GBM cell lines reconstituted with IDO wild-type or IDO enzyme-null cDNA were created and validated in vitro and in vivo Microarray analysis was conducted to search for genes that IDO regulates, followed by the analysis of human GBM cell lines, patient GBM and plasma, and the TCGA database. Ex vivo cell co-culture assays, syngeneic and humanized mouse GBM models were used to test the alternative hypothesis. Results Non-enzymic tumor cell IDO activity decreased the survival of experimental animals and increased the expression of complement factor H (CFH) and its isoform, factor H like protein 1 (FHL-1) in human GBM. Tumor cell IDO increased CFH and FHL-1 expression independent of tryptophan metabolism. Increased intratumoral CFH and FHL-1 levels were associated with poorer survival among glioma patients. Similar to IDO effects, GBM cell FHL-1 expression increased intratumoral Tregs and MDSCs while it decreased overall survival in mice with GBM. Conclusions Our study reveals a newly non-metabolic IDO-mediated enhancement of CFH expression and provides a new therapeutic target in patients with GBM.