Pluto Bioinformatics

GSE130679: Tumor endothelial up-regulation of IDO1 limits the response to CD40-stimulating immunotherapy

Bulk RNA sequencing

CD40-stimulating immunotherapy elicits potent anti-tumor responses, which are mainly T-cell dependent. Here, we have investigated how tumor endothelial cells respond to CD40-stimulating immunotherapy by isolating endothelial cells from B16.F10 melanoma in anti-CD40 treated or isotype treated mice followed by RNA-sequencing. Gene set enrichment analysis revealed an increase in interferon- related responses in tumor endothelial cells following anti-CD40 therapy. The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) was preferentially expressed in endothelial cells, and it was up-regulated upon anti-CD40 treatment. IDO1 expression in tumor endothelium was positively correlated to T-cell infiltration and to increased expression of IFN in the tumor microenvironment. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFN, but not in response to CD40-stimulation. Combining agonistic anti-CD40 therapy with the IDO1 inhibitor epacadostat delayed tumor growth and increased survival in B16.F10 tumor-bearing mice, which was associated with increased activation of tumor-infiltrating T-cells. Hereby, we have uncovered an immunosuppressive feedback mechanism, in which tumor vessels limit the efficacy of cancer immunotherapy by up-regulating IDO1 in response to T-cell activation. SOURCE: Joachim Schultze (j.schultze@uni-bonn.de) - LIMES (Life and Medical Sciences Center Genomics and Immunoregulation)