TY - JOUR
T1 - Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses
AU - Odunsi, Kunle
AU - Qian, Feng
AU - Lugade, Amit A.
AU - Yu, Han
AU - Geller, Melissa A.
AU - Fling, Steven P.
AU - Kaiser, Judith C.
AU - Lacroix, Andreanne M.
AU - D'Amico, Leonard
AU - Ramchurren, Nirasha
AU - Morishima, Chihiro
AU - Disis, Mary L.
AU - Dennis, Lucas
AU - Danaher, Patrick
AU - Warren, Sarah
AU - Nguyen, Van Anh
AU - Ravi, Sudharshan
AU - Tsuji, Takemasa
AU - Rosario, Spencer
AU - Zha, Wenjuan
AU - Hutson, Alan
AU - Liu, Song
AU - Lele, Shashikant
AU - Zsiros, Emese
AU - McGray, A. J.Robert
AU - Chiello, Jessie
AU - Koya, Richard
AU - Chodon, Thinle
AU - Morrison, Carl D.
AU - Putluri, Vasanta
AU - Putluri, Nagireddy
AU - Mager, Donald E.
AU - Gunawan, Rudiyanto
AU - Cheever, Martin A.
AU - Battaglia, Sebastiano
AU - Matsuzaki, Junko
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/3/16
Y1 - 2022/3/16
N2 - 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+), which reduced T cell proliferation and function. Because NAD+ metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD+ on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD+-mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.
AB - 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+), which reduced T cell proliferation and function. Because NAD+ metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD+ on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD+-mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.
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U2 - 10.1126/scitranslmed.abg8402
DO - 10.1126/scitranslmed.abg8402
M3 - Article
C2 - 35294258
AN - SCOPUS:85126670511
SN - 1946-6234
VL - 14
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 636
M1 - abg8402
ER -