Odunsi et al. performed metabolomic and transcriptomic analyses of pre- and post-treatment tumors from patients with ovarian cancer treated with the IDO1 inhibitor, epacadostat (EPA). IDO1 inhibition efficiently blocked the Kyn pathway in tumor cells, but resulted in elevation of serotonin and Nic/NAD+ generation, which via A2a and A2b purinergic receptors, reduced T cell proliferation and function. Combination of EPA and A2a/A2b purinergic receptor blockade resulted in an increased T cell infiltrative immune signature and improved survival in an IDO1-overexpressing preclinical mouse model of ovarian cancer.
Contributed by Shishir Pant
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.
Author Info: (1) University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA. Center for Immun
Author Info: (1) University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA. Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (2) University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA. Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 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) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (8) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (9) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (10) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (11) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. (12) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (13) NanoString Technologies Inc., Seattle, WA, USA. (14) NanoString Technologies Inc., Seattle, WA, USA. (15) NanoString Technologies Inc., Seattle, WA, USA. (16) Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA. (17) Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA. (18) University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA. Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (19) Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (20) Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (21) Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (22) Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (23) Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (24) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (25) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (26) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (27) University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA. Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (28) University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA. Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (29) Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (30) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. (31) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. (32) Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA. Enhanced Pharmacodynamics LLC, Buffalo, NY, USA. (33) Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA. (34) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (35) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (36) University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA. Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
