Cited by 838Immunotherapy and Immune ResponsesImmune Response and InflammationCancer Immunotherapy and Biomarkers

Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1

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Chiba, Shigeki, Baghdadi, Muhammad, Akiba, Hisaya, Yoshiyama, Hironori, Kinoshita, Ichiro, Dosaka-Akita, Hirotoshi, Fujioka, Yoichiro, Ohba, Yusuke +7 more·2012·Nature Immunology

Abstract

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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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
Venue
Nature Immunology
Published
2012-07-29
Volume
13
Issue
9
Pages
832-842
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
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
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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