Document Detail

Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1.
MedLine Citation:
PMID:  22842346     Owner:  NLM     Status:  MEDLINE    
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.
Shigeki Chiba; Muhammad Baghdadi; Hisaya Akiba; Hironori Yoshiyama; Ichiro Kinoshita; Hirotoshi Dosaka-Akita; Yoichiro Fujioka; Yusuke Ohba; Jacob V Gorman; John D Colgan; Mitsuomi Hirashima; Toshimitsu Uede; Akinori Takaoka; Hideo Yagita; Masahisa Jinushi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-29
Journal Detail:
Title:  Nature immunology     Volume:  13     ISSN:  1529-2916     ISO Abbreviation:  Nat. Immunol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-23     Completed Date:  2012-10-26     Revised Date:  2014-11-14    
Medline Journal Info:
Nlm Unique ID:  100941354     Medline TA:  Nat Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  832-42     Citation Subset:  IM    
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MeSH Terms
Dendritic Cells / immunology*,  metabolism
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
HMGB1 Protein / immunology*,  metabolism
Immunity, Innate*
Immunologic Surveillance / immunology
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*
Grant Support
Reg. No./Substance:
0/HMGB1 Protein; 0/Havcr2 protein, mouse; 0/Nucleic Acids; 0/Receptors, Pattern Recognition; 0/Receptors, Virus
Comment In:
Nat Rev Immunol. 2012 Sep;12(9):620-1   [PMID:  22918461 ]
Nat Immunol. 2012 Sep;13(9):808-10   [PMID:  22910384 ]
Nat Rev Cancer. 2012 Sep;12(9):584   [PMID:  22918413 ]

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