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

被引：778

作者：

Chiba, Shigeki ^{[1
]}

Baghdadi, Muhammad ^{[1
,2
,3
]}

Akiba, Hisaya ^{[4
]}

Yoshiyama, Hironori ^{[1
]}

Kinoshita, Ichiro ^{[3
]}

Dosaka-Akita, Hirotoshi ^{[3
]}

Fujioka, Yoichiro ^{[5
]}

Ohba, Yusuke ^{[5
]}

Gorman, Jacob V. ^{[6
]}

Colgan, John D. ^{[6
]}

Hirashima, Mitsuomi ^{[7
]}

Uede, Toshimitsu ^{[8
]}

Takaoka, Akinori ^{[2
]}

Yagita, Hideo ^{[4
]}

Jinushi, Masahisa ^{[1
]}

机构：

[1] Hokkaido Univ, Inst Med Genet, Res Ctr Infect Associated Canc, Sapporo, Hokkaido, Japan

[2] Hokkaido Univ, Inst Med Genet, Div Signaling Canc & Immunol, Sapporo, Hokkaido, Japan

[3] Hokkaido Univ, Grad Sch Med, Dept Med Oncol, Sapporo, Hokkaido, Japan

[4] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan

[5] Hokkaido Univ, Grad Sch Med, Dept Pathophysiol & Signal Transduct, Sapporo, Hokkaido, Japan

[6] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA

[7] Kagawa Univ, Fac Med, Dept Immunol & Immunopathol, Takamatsu, Kagawa 760, Japan

[8] Hokkaido Univ, Inst Med Genet, Div Mol Immunol, Sapporo, Hokkaido, Japan

来源：

NATURE IMMUNOLOGY | 2012年 / 13卷 / 09期

关键词：

DENDRITIC CELLS; TOLL-LIKE; RIG-I; ANTITUMOR IMMUNITY; T-CELLS; INFLAMMATION; BINDING; PHOSPHATIDYLSERINE; PHAGOCYTOSIS; ACTIVATION;

D O I：

10.1038/ni.2376

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：832 / 842

页数：11

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