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Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1
Open accessAbstract
The mechanisms by which tumor microenvironments modulate nucleic acid-mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor-associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids.
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“In line with this notion, the enzymatic degradation of extracellular nucleic acids considerably limits the immunogenicity of RCD [864, 875].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [875]
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Metadata
- Authors
- Chiba, S., Baghdadi, M., Akiba, H., Yoshiyama, H., Kinoshita, I., Dosaka-Akita, H., Fujioka, Y., Ohba, Y., Gorman, J. V., Colgan, J. D., Hirashima, M., Uede, T., Takaoka, A., Yagita, H., & Jinushi, M.
- Affiliations
- Hokkaido University (JP)
- Juntendo University (JP)
- University of Iowa (US)
- Kagawa University (JP)
- Corresponding author
- Jinushi, Masahisa
- ORCID
- Venue
- Nature Immunology
- Published
- 2012-07-29
- Volume
- 13
- Issue
- 9
- Pages
- 832-842
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3622453
- OpenAlex
- W2112400160
- Cited by
- 838
- References
- 50
- Citations by year
- 2026: 40 · 2025: 53 · 2024: 81 · 2023: 82 · 2022: 83 · 2021: 80 · 2020: 65 · 2019: 63 · 2018: 56 · 2017: 48 · 2016: 53 · 2015: 41 · 2014: 39 · 2013: 39 · 2012: 15
- FWCI
- 18.74
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (23590534, 23591132, 23501283, 22590360, 23390090, 22591098, 22240089, 23659196, 21390113)
- National Institute of Allergy and Infectious Diseases (R01AI093737, R01AI067489)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- TIM-3, HMGB1, tumor-associated dendritic cells, nucleic acid sensing, innate immunity, tumor microenvironment, Toll-like receptors, galectin-9, DNA vaccine, chemotherapy, antitumor immunity, alarmins
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, Dendritic Cells, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Immunity, Innate, Immunologic Surveillance, Mice, Inbred C57BL, Microscopy, Fluorescence, Neoplasms, Nucleic Acids, Receptors, Virus, Immunoblotting, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, HMGB1 Protein, Receptors, Pattern Recognition, Mice, Tumor Microenvironment
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