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Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy
Abstract
Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-kappaB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.
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“Studies of IDO pathway blockade with radiation, chemotherapy and tumor vaccines suggest an improvement relative to those treatments alone (53,54).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [53]
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Metadata
- Authors
- Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E., & Prendergast, G. C.
- Affiliations
- Lankenau Institute for Medical Research (US)
- Thomas Jefferson University (US)
- Corresponding author
- Prendergast, George C
- Venue
- Nature Medicine
- Published
- 2005-02-13
- Volume
- 11
- Issue
- 3
- Pages
- 312-319
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2090410108
- Cited by
- 1,064
- References
- 54
- Citations by year
- 2026: 12 · 2025: 29 · 2024: 41 · 2023: 53 · 2022: 45 · 2021: 53 · 2020: 59 · 2019: 59 · 2018: 65 · 2017: 72 · 2016: 54 · 2015: 63 · 2014: 51 · 2013: 53 · 2012: 56
- FWCI
- 23.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- indoleamine 2,3-dioxygenase, BIN1, IDO inhibitors, tumor immune evasion, antitumor immunity, STAT1, NF-κB, MMTV-Neu mice, breast cancer, combination chemotherapy, tumor immunosuppression, gene knockout
- MeSH terms
- Animals, Cell Transformation, Neoplastic, DNA-Binding Proteins, Drug Synergism, Enzyme Inhibitors, Indoles, Interferon-gamma, Mammary Neoplasms, Experimental, Molecular Sequence Data, Nerve Tissue Proteins, Thiohydantoins, Tryptophan Oxygenase, Trans-Activators, NF-kappa B, Paclitaxel, Tumor Escape, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, Indoleamine-Pyrrole 2,3,-Dioxygenase, STAT1 Transcription Factor, Mice, Rats
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