Targeting Indoleamine 2,3-Dioxygenase in Cancer Models Using the Novel Small Molecule Inhibitor NTRC 3883-0
| Autor: | Anne M. van Altena, Leon F.A.G. Massuger, Winfried R. Mulder, Diep Vu-Pham, Joeri de Wit, Freek van Cauter, Yvonne Grobben, Judith E. den Ouden, Jos de Man, Antoon M. van Doornmalen, Joost C.M. Uitdehaag, Nicole Willemsen-Seegers, Jan Gerard Sterrenburg, Rogier C. Buijsman, Guido J.R. Zaman, Michelle Muller, Martine B.W. Prinsen |
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| Rok vydání: | 2020 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
indoleamine 2 3-dioxygenase T cell medicine.medical_treatment Cell Immunology Melanoma Experimental CD8-Positive T-Lymphocytes Small Molecule Libraries Mice Immune system IDO1 inhibitor All institutes and research themes of the Radboud University Medical Center Cancer immunotherapy In vivo Cell Line Tumor medicine Immunology and Allergy Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Indoleamine 2 3-dioxygenase Kynurenine Original Research Cell Proliferation cancer immunotherapy immunosuppression Chemistry Tryptophan Cancer medicine.disease Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] medicine.anatomical_structure ovarian cancer Cell culture Cancer research syngeneic mouse model lcsh:RC581-607 |
| Zdroj: | Frontiers in Immunology, 11 Frontiers in Immunology Frontiers in Immunology, Vol 11 (2021) |
| ISSN: | 1664-3224 |
| Popis: | Indoleamine 2,3-dioxygenase (IDO1) is a key regulator of immune suppression by catalyzing the oxidation of L-tryptophan. IDO1 expression has been related to poor prognosis in several cancers and to resistance to checkpoint immunotherapies. We describe the characterization of a novel small molecule IDO1 inhibitor, NTRC 3883-0, in a panel of biochemical and cell-based assays, and various cancer models. NTRC 3883-0 released the inhibitory effect of IDO1 on CD8-positive T cell proliferation in co-cultures of IDO1-overexpressing cells with healthy donor lymphocytes, demonstrating its immune modulatory activity. In a syngeneic mouse model using IDO1-overexpressing B16F10 melanoma cells, NTRC 3883-0 effectively counteracted the IDO1-induced modulation of L-tryptophan and L-kynurenine levels, demonstrating its in vivo target modulation. Finally, we studied the expression and activity of IDO1 in primary cell cultures established from the malignant ascites of ovarian cancer patients. In these cultures, IDO1 expression was induced upon stimulation with IFNγ, and its activity could be inhibited by NTRC 3883-0. Based on these results, we propose the use of ascites cell-based functional assays for future patient stratification. Our results are discussed in light of the recent discontinuation of clinical trials of more advanced IDO1 inhibitors and the reconsideration of IDO1 as a valid drug target. |
| Databáze: | OpenAIRE |
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