ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 109 citations in OpenAlex.
- Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial.Journal for immunotherapy of cancer · 2017Trial
- Neoadjuvant BO-112 and Hypofractionated Radiation Therapy with or without Nivolumab in Soft-Tissue Sarcoma: Preclinical and Phase I Results.Cancer discovery · 2026Article
- Assessment of Fecal Microbiota in Healthy Dogs and Dogs with Cutaneous Mast Cell Tumors Treated with Electrochemotherapy Combined with Gene Electrotransfer of IL-12.Veterinary sciences · 2026Article
- Updates on radiotherapy-immunotherapy combinations: Proceedings of 8th Annual ImmunoRad Conference.Oncoimmunology · 2025Article
- Metabolites as agents and targets for cancer immunotherapy.Nature reviews. Drug discovery · 2025Review
- Proceedings of the National Cancer Institute Workshop on combining immunotherapy with radiotherapy: challenges and opportunities for clinical translation.The Lancet. Oncology · 2025Article
- Radiotherapy as salvage therapy and an adjunct to immunotherapy: exploring local and abscopal mechanisms to overcome immunotherapy resistance: a narrative review.Translational lung cancer research · 2025Review
- Wellness-enhancing effects of the canine growth hormone releasing hormone therapy mediated by plasmid and electroporation in healthy old dogs.Frontiers in veterinary science · 2025Article
- Radiation drives tertiary lymphoid structures to reshape TME for synergized antitumour immunity.Expert reviews in molecular medicine · 2024Review
- Immunohistochemical and transcriptomic characterization of T and myeloid cell infiltrates in canine malignant melanoma.Veterinary and comparative oncology · 2024Article
- Review
- Radiotherapy Combined with Intralesional Immunostimulatory Agents for Soft Tissue Sarcomas.Seminars in radiation oncology · 2024Review
- Companion Animals as a Key to Success for Translating Radiation Therapy Research into the Clinic.Cancers · 2023Review
- The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer.Frontiers in oral health · 2023Review
- Indoleamine 2,3-dioxygenase gene expression and kynurenine to tryptophan ratio correlation with nasopharyngeal carcinoma progression and survival.Immunity, inflammation and disease · 2022Article
- Robust immune response stimulated by in situ injection of CpG/αOX40/cGAMP in αPD-1-resistant malignancy.Cancer immunology, immunotherapy : CII · 2022Article
- Review
- Targeting Indoleamine Dioxygenase and Tryptophan Dioxygenase in Cancer Immunotherapy: Clinical Progress and Challenges.Drug design, development and therapy · 2022Review
- Radiotherapy induced immunogenic cell death by remodeling tumor immune microenvironment.Frontiers in immunology · 2022Review
- Dynamic change of IDO1 activity predicts survival in patients with unresectable stage III NSCLC and chemoradiotherapy.Frontiers in immunology · 2022Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
purposePrevious studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. EXPERIMENTAL
designWe examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial.
resultsIn murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects.
conclusionsThese results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. ©2016 AACR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.