Targeting Indoleamine 2,3-Dioxygenase in Cancer Models Using the Novel Small Molecule Inhibitor NTRC 3883-0.

Autor:	Grobben Y; Netherlands Translational Research Center B.V., Oss, Netherlands., de Man J; Netherlands Translational Research Center B.V., Oss, Netherlands., van Doornmalen AM; Netherlands Translational Research Center B.V., Oss, Netherlands., Muller M; Netherlands Translational Research Center B.V., Oss, Netherlands., Willemsen-Seegers N; Netherlands Translational Research Center B.V., Oss, Netherlands., Vu-Pham D; Netherlands Translational Research Center B.V., Oss, Netherlands., Mulder WR; Netherlands Translational Research Center B.V., Oss, Netherlands., Prinsen MBW; Netherlands Translational Research Center B.V., Oss, Netherlands., de Wit J; Netherlands Translational Research Center B.V., Oss, Netherlands., Sterrenburg JG; Netherlands Translational Research Center B.V., Oss, Netherlands., van Cauter F; Netherlands Translational Research Center B.V., Oss, Netherlands., den Ouden JE; Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands., van Altena AM; Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands., Massuger LF; Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands., Uitdehaag JCM; Netherlands Translational Research Center B.V., Oss, Netherlands., Buijsman RC; Netherlands Translational Research Center B.V., Oss, Netherlands., Zaman GJR; Netherlands Translational Research Center B.V., Oss, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Jan 28; Vol. 11, pp. 609490. Date of Electronic Publication: 2021 Jan 28 (Print Publication: 2020).
DOI:	10.3389/fimmu.2020.609490
Abstrakt:	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. Competing Interests: RB and GZ are managing directors and shareholders of Netherlands Translational Research Center B.V. YG, JM, AD, MM, NW-S, DV-P, WM, MP, JW, JS, FC and JU were employed by Netherlands Translational Research Center B.V. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Grobben, de Man, van Doornmalen, Muller, Willemsen-Seegers, Vu-Pham, Mulder, Prinsen, de Wit, Sterrenburg, van Cauter, den Ouden, van Altena, Massuger, Uitdehaag, Buijsman and Zaman.)
Databáze:	MEDLINE
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