Abstract 1849: Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) catalyze the oxidation of L-Tryptophan (TRP) leading to the formation of immunosuppressive kynurenine (KYN) pathway metabolites. According to TCGA, a substantial fraction of different tumor types expresses both IDO1 and TDO2. In 82 tumor samples (GBM, hepatocellular carcinoma, NSCLC, and ovarian cancer) analyzed for IDO1/TDO2 RNA expression (RNA sequencing) and TRP metabolite content (LC-MS/MS), we found TDO2 highly expressed in hepatocellular carcinoma and to lower levels in NSCLC and ovarian cancer. IDO1 was found to be expressed in NSCLC and ovarian cancer but at higher levels and its expression was correlating with KYN levels. Immunosuppressive properties of KYN and downstream metabolites are mediated through T cell apoptosis and regulatory T cell (Treg) induction. In our hands, KYN at concentrations ≥ 50uM was shown to be immunosuppressive, notably inducing T cell apoptosis. According to our and published data, such high KYN concentrations (≥ 50uM) can be found in a subset of human tumors. As outlined, both IDO1 and TDO2 can contribute to high KYN levels in tumors. Hence, dual IDO1/TDO2 inhibition should be superior in decreasing tumor KYN levels and levering immunosuppression as compared to IDO1 selective inhibition. In this regard, we have generated potent dual IDO1/TDO2 inhibitors inhibiting IDO1 and TDO2 enzyme activity in cellular assays in vitro. To prove the concept of superiority in vivo, we established a dual IDO1/TDO2 expressing human tumor model (LOVO+IFNg) in the mouse and showed that the oral administration of a dual IDO1/TDO2 inhibitor as compared to an IDO1 selective inhibitor showed enhanced KYN/TRP modulation in the tumor. Lead compounds with favorable drug-like properties are currently investigated for pre-clinical development. Citation Format: Carina Lotz-Jenne, Sylvaine Cren, Christoph Joesch, Sabine Ackerknecht, Jennifer Brandes, Claire Moebs, Dominik Hartl, Felix Hartrampf, Philippe Guerry, Julien Pothier, Alexia Chavanton-Arpel. Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1849.