Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy

摘要: CD40-stimulating immunotherapy can elicit potent anti-tumor responses by activating dendritic cells and enhancing T-cell priming. Tumor vessels orchestrate recruitment during immune response, but the effect of on tumor endothelial has not been evaluated. Here, we have investigated how transcriptionally respond to isolating from agonistic CD40 mAb- or isotype-treated mice bearing B16-F10 melanoma, performing RNA-sequencing. Gene set enrichment analysis revealed that mAb therapy increased interferon (IFN)-related in cells, including up-regulation immunosuppressive enzyme Indoleamine 2, 3-Dioxygenase 1 (IDO1). IDO1 was predominantly expressed within microenvironment, its expression endothelium positively correlated infiltration intratumoral IFNγ. In vitro, up-regulated response T-cell-derived IFNγ, CD40-stimulation. Combining with inhibitor epacadostat delayed growth associated activation tumor-infiltrating T-cells. Hereby, show up-regulate upon IFNγ-secretion T-cells, revealing a novel feedback mechanism whereby limit activation.