IMMU-10. RADIOTHERAPY AND PD-1 BLOCKADE INCREASES TRYPTOPHAN METABOLISM IN BRAIN TUMOR-DRAINING SECONDARY LYMPHOID ORGANS
| Autor: | Derek A. Wainwright, Sebastian Otto-Meyer, Erik Ladomersky, Kristen L. Lauing, Lijie Zhai, Alicia Lenzen, Rohan Savoor, Rimas V. Lukas |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Cancer Research
medicine.drug_class business.industry medicine.medical_treatment Brain tumor Tryptophan Spleen Metabolism Tryptophan Metabolism Monoclonal antibody medicine.disease Radiation therapy chemistry.chemical_compound Abstracts medicine.anatomical_structure Oncology chemistry Cancer research medicine Neurology (clinical) business Kynurenine |
| Popis: | 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 × 10(5)syngeneic 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 |
| Databáze: | OpenAIRE |
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