Authors: Kunle Odunsi, Feng Qian, Amit A. Lugade, Han Yu, Melissa A. Geller, Steven P. Fling, Judith C. Kaiser, Andreanne M. Lacroix, Leonard D’Amico, Nirasha Ramchurren, Chihiro Morishima, Mary L. Disis, Lucas Dennis, Patrick Danaher, Sarah Warren, Van Anh Nguyen, Sudharshan Ravi, Takemasa Tsuji, Spencer Rosario, Wenjuan Zha, Alan Hutson, Song Liu, Shashikant Lele, Emese Zsiros, A. J. Robert McGray, Jessie Chiello, Richard Koya, Thinle Chodon, Carl D. Morrison, Vasanta Putluri, Nagireddy Putluri, Donald E. Mager, Rudiyanto Gunawan, Martin A. Cheever, Sebastiano Battaglia, Junko Matsuzaki
Published: 2022-03-16
DOI: 10.1126/scitranslmed.abg8402
Source: Full article
To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. IDO1 inhibition resulted in efficient blockade of the kynurenine pathway of tryptophan degradation and was accompanied by a metabolic adaptation that shunted tryptophan catabolism toward the serotonin pathway. This resulted in elevated nicotinamide adenine dinucleotide (NAD