IMMU-10. RADIOTHERAPY AND PD-1 BLOCKADE INCREASES TRYPTOPHAN METABOLISM IN BRAIN TUMOR-DRAINING SECONDARY LYMPHOID ORGANS

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 20; no. suppl_6; p. vi123
• Main Authors: Savoor, Rohan, Ladomersky, Erik, Otto-Meyer, Sebastian, Zhai, Lijie, Lauing, Kristen, Lenzen, Alicia, Lukas, Rimas, Wainwright, Derek
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 05.11.2018
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noy148.513

Abstract INTRODUCTION Glioblastoma (GBM) is an aggressive, incurable, primary brain tumor with a median survival of 15–20 months. High intratumoral expression of indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme that metabolizes tryptophan (Trp) into kynurenine (Kyn), is one factor that contributes to immunosuppression in GBM. Unexpectedly, we discovered that IDO1 enzyme activity becomes targetable in non-tumor cells after treatment with brain tumor radiation (RT) and PD-1 mAb (Ladomersky et al., 2018; CCR). The premise for this investigation is to evaluate IDO1 enzyme activity before and after radiation and PD-1 blockade, for the identification of non-brain tumor tissues that are active for immunosuppressive tryptophan metabolism. METHODS Wild-type (WT) and IDO1 knockout mice (IDO1KO) were intracranially-injected (ic.) with 2 × 105syngeneic GL261. At two weeks post-ic., mice were treated with RT (n=10/group) or PD-1 mAb. Mice were euthanized at day one (n=5/group) or day seven, following treatment (n=5/group). IDO1 metabolism was evaluated by HPLC for Trp and Kyn levels in the brain tumor, contralateral non-tumor brain, cervical lymph nodes and spleen. RESULTS Radiation had an early effect at increasing the Kyn/Trp ratio, a proxy for IDO1 enzyme activity, in normal brain and draining lymph nodes (P<0.01). Interestingly, PD-1 blockade also led to an early increase in the Kyn/Trp ratio of lymph nodes (P<0.01), but not in normal brain. In contrast, spleen showed a late increase in the Kyn/Trp ratio (P<0.01). Strikingly, the majority of Kyn/Trp ratio changes were observed both in WT and IDO1KO mice. CONCLUSION Our data suggest a systemic and tissue-selective change in Trp metabolism after radiation and PD-1 blockade. Unexpectedly, many of these changes were not specific to IDO1, suggesting a therapeutic inducibility of other immunosuppressive mediators, such as tryptophan dioxygenase (TDO). These data suggest that, effectively inhibiting tryptophan metabolism in subjects with brain tumors will likely require dual IDO1/TDO inhibition.