Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy
Maria Georganaki, Mohanraj Ramachandran, Sander Tuit, Nicolás Gonzalo Núñez, Alexandros Karampatzakis, Grammatiki Fotaki, Luuk van Hooren, Hua Huang, Roberta Lugano, Thomas Ulas, Aura Kaunisto, Eric C. Holland, Peter Ellmark, Sara M. Mangsbo, Joachim L. Schultze, Magnus Essand, Sònia Tugues, Anna Dimberg
Abstract
, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth in B16-F10 melanoma, associated with increased activation of tumor-infiltrating T-cells. Hereby, we show that the tumor endothelial cells up-regulate IDO1 upon CD40-stimulating immunotherapy in response to increased IFNγ-secretion by T-cells, revealing a novel immunosuppressive feedback mechanism whereby tumor vessels limit T-cell activation.