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Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses.
- Source :
- Science Translational Medicine; 3/16/2022, Vol. 14 Issue 636, p1-15, 15p
- Publication Year :
- 2022
-
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<superscript>+</superscript>), which reduced T cell proliferation and function. Because NAD<superscript>+</superscript> metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD<superscript>+</superscript> 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<superscript>+</superscript>-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. Saying "I DO" to combination therapy: Indoleamine 2,3-dioxygenase 1 (IDO1) drives immunosuppression in high-grade serous ovarian cancer. Inhibition of IDO1 in combination with chemotherapy has shown limited efficacy in clinical trials. Here, Odunsi et al. treated patients with the IDO1 inhibitor epacadostat and studied the effect on the tumor microenvironment (TME) in tumor biopsies. IDO1 inhibition increased nicotinamide adenine dinucleotide (NAD<superscript>+</superscript>), which reduced T cell function in the TME. Combining epacadostat with purinergic receptor antagonists rescued T cell proliferation in a mouse model of ovarian cancer. These findings highlight the potential downside of IDO1 inhibition and suggest that IDO1 inhibitor therapy will require combination with NAD<superscript>+</superscript> signaling blockade. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19466234
- Volume :
- 14
- Issue :
- 636
- Database :
- Complementary Index
- Journal :
- Science Translational Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 155756087
- Full Text :
- https://doi.org/10.1126/scitranslmed.abg8402