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PMID: 22842346 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature immunology ·Vol. 13 ·No. 9 ·2012-09-00 ·Pages 832-42

Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, Hirashima M, Uede T, Takaoka A, Yagita H, Jinushi M

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.

MeSH Terms
Animals Dendritic Cells/immunology,metabolism Enzyme-Linked Immunosorbent Assay Flow Cytometry HMGB1 Protein/immunology,metabolism Hepatitis A Virus Cellular Receptor 2 Humans Immunity, Innate Immunoblotting Immunologic Surveillance/immunology Mice Mice, Inbred C57BL Microscopy, Confocal Microscopy, Fluorescence Neoplasms/immunology,metabolism Nucleic Acids/immunology Receptors, Pattern Recognition/immunology Receptors, Virus/immunology,metabolism Reverse Transcriptase Polymerase Chain Reaction Tumor Microenvironment/immunology
Chemicals
HMGB1 Protein Havcr2 protein, mouse Hepatitis A Virus Cellular Receptor 2 Nucleic Acids Receptors, Pattern Recognition Receptors, Virus
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Chiba Shigeki
Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Baghdadi Muhammad
Akiba Hisaya
Yoshiyama Hironori
Kinoshita Ichiro
Dosaka-Akita Hirotoshi
Fujioka Yoichiro
Ohba Yusuke
Gorman Jacob V
Colgan John D
Hirashima Mitsuomi
Uede Toshimitsu
Takaoka Akinori
Yagita Hideo
Jinushi Masahisa
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.2376
Published
2012-09-00
Epub
2012-00-29
Pages
832-42
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC3622453
Subset
IM
Grants
NIAID NIH HHS · R01 AI067489 · United States
NIAID NIH HHS · R01 AI093737 · United States
Corrections
CommentIn
PMID: 22910384
CommentIn
PMID: 22918413
CommentIn
PMID: 22918461
External Links
PubMed source DOI: 10.1038/ni.2376 PMC Full Text View journal details
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