You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (PD49)1 Sep 2021PD49-05 TRYPTOPHAN 2,3-DIOXYGENASE IN TUMOR CELLS IS ASSOCIATED WITH KYNURENINE ACCUMULATION AND RESISTANCE TO IMMUNOTHERAPY IN RENAL CELL CARCINOMA Makoto Sumitomo, Kenji Zennami, Kiyoshi Takahara, Masashi Takenaka, Takuhisa Nukaya, Kosuke Fukaya, Manabu Ichino, Hitomi Sasaki, and Ryoichi Shiroki Makoto SumitomoMakoto Sumitomo More articles by this author , Kenji ZennamiKenji Zennami More articles by this author , Kiyoshi TakaharaKiyoshi Takahara More articles by this author , Masashi TakenakaMasashi Takenaka More articles by this author , Takuhisa NukayaTakuhisa Nukaya More articles by this author , Kosuke FukayaKosuke Fukaya More articles by this author , Manabu IchinoManabu Ichino More articles by this author , Hitomi SasakiHitomi Sasaki More articles by this author , and Ryoichi ShirokiRyoichi Shiroki More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002071.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme associated with immunomodulation through its regulation of the tryptophan (Trp)-kynurenine (Kyn) pathway in advanced cancers, including metastatic renal cell carcinoma (mRCC). However, the failure of IDO1 inhibitors when used in combination with immune checkpoint inhibitors (ICIs), as observed in clinical trials, raises a number of questions. This study aimed to investigate the association of tryptophan 2,3-dioxygenase (TDO) and IDO1 with cancer development and resistance to immunotherapy in patients with RCC. METHODS: Tumor (T) and non-tumor (N) tissues as well as serum samples were obtained from 66 RCC patients. Metabolome analyses were performed by liquid chromatography mass spectrometry (LC/MS). Important metabolites including Trp and Kyn were analyzed and the Kyn/Trp ratio (KTR) was calculated. The protein expression of Kyn, IDO1, TDO, and other immune inhibitory molecules, such as PD-L1, forkhead box P3 (FOXP3), was evaluated by immunohistochemistry (IHC) using formalin-fixed, paraffin-embedded sections of surgical specimens obtained from 40 mRCC patients who received ICI-based immunotherapy. RESULTS: The tissue Kyn T/N ratio rather than the serum KTR was strongly associated with RCC staging. In mRCC patients, TDO rather than IDO1 was expressed in the RCC tumor cells, showing a strong association with Kyn expression. In the Kaplan–Meier analysis of progression-free survival (PFS) according to ICI treatment, the TDO expression level high group had significantly poorer prognosis (median PFS, 4.9 months; 95% CI: 1.4–5.4) than the TDO expression level low group (median PFS, 14.3 months; 95% CI: 7.0–NA; p <0.001). In the multivariate analysis, TDO expression levels remained associated with PFS (HR=3.967, 95% CI: 1.600-9.833; P <0.001). CONCLUSIONS: Our results suggest that TDO expression in tumor cells is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in RCC patients. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e846-e846 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Makoto Sumitomo More articles by this author Kenji Zennami More articles by this author Kiyoshi Takahara More articles by this author Masashi Takenaka More articles by this author Takuhisa Nukaya More articles by this author Kosuke Fukaya More articles by this author Manabu Ichino More articles by this author Hitomi Sasaki More articles by this author Ryoichi Shiroki More articles by this author Expand All Advertisement Loading ...