Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses

Sci Transl Med. 2022 Mar 16;14(636):eabg8402. doi: 10.1126/scitranslmed.abg8402.

Kunle Odunsi ¹ ² ³, Feng Qian ¹ ² ³, Amit A Lugade ³, Han Yu ⁴, Melissa A Geller ⁵, Steven P Fling ⁶, Judith C Kaiser ⁶, Andreanne M Lacroix ⁶, Leonard D'Amico ⁶, Nirasha Ramchurren ⁶, Chihiro Morishima ⁶ ⁷, Mary L Disis ⁶, Lucas Dennis ⁸, Patrick Danaher ⁸, Sarah Warren ⁸, Van Anh Nguyen ⁹, Sudharshan Ravi ¹⁰, Takemasa Tsuji ¹ ² ³, Spencer Rosario ⁴, Wenjuan Zha ⁴, Alan Hutson ⁴, Song Liu ⁴, Shashikant Lele ¹¹, Emese Zsiros ³ ¹¹, A J Robert McGray ³, Jessie Chiello ³, Richard Koya ¹ ² ³, Thinle Chodon ¹ ² ³, Carl D Morrison ¹², Vasanta Putluri ¹³, Nagireddy Putluri ¹³, Donald E Mager ⁹ ¹⁴, Rudiyanto Gunawan ¹⁰, Martin A Cheever ⁶, Sebastiano Battaglia ³, Junko Matsuzaki ¹ ² ³

Affiliations

1 University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.
2 Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA.
3 Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
4 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
5 Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN, USA.
6 Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
7 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
8 NanoString Technologies Inc., Seattle, WA, USA.
9 Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
10 Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA.
11 Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
12 Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
13 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
14 Enhanced Pharmacodynamics LLC, Buffalo, NY, USA.

PMID: 35294258 DOI: 10.1126/scitranslmed.abg8402

Abstract

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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