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ATM-Mediated DNA Damage Signals Mediate Immune Escape through Integrin-αvβ3-Dependent Mechanisms

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Title: ATM-Mediated DNA Damage Signals Mediate Immune Escape through Integrin-αvβ3-Dependent Mechanisms
Authors: Jinushi, Masahisa Browse this author
Chiba, Shigeki Browse this author
Baghdadi, Muhammad Browse this author
Kinoshita, Ichiro Browse this author →KAKEN DB
Dosaka-Akita, Hirotoshi Browse this author
Ito, Koyu Browse this author
Yoshiyama, Hironori Browse this author →KAKEN DB
Yagita, Hideo Browse this author
Uede, Toshimitsu Browse this author →KAKEN DB
Takaoka, Akinori Browse this author →KAKEN DB
Keywords: Integrin-αvβ3
DNA damage response
Antitumor immunity
Issue Date: 1-Jan-2012
Publisher: American Association for Cancer Research
Journal Title: Cancer Research
Volume: 72
Issue: 1
Start Page: 56
End Page: 65
Publisher DOI: 10.1158/0008-5472.CAN-11-2028
PMID: 22094875
Abstract: Although recent evidences have been unveiling the critical role of tumor microenvironments in tumor progression and metastasis, it remains unclear how resistance to various anticancer modalities is linked with the modulation of tumor microenvironments. We identified a novel mechanism whereby constitutively activated DNA damage signals in anticancer therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvβ3-dependent manner. Integrin-αvβ3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/chk2-and NF-κB-mediated pathways. The inhibition of tumor-specific integrin-αvβ3 improved therapeutic efficacies of anticancer drugs by stimulating endogenous host immune systems. As a mechanism of action, tumor-specific integrin-αvβ3 targets dendritic cells to facilitate phagocytosis of live resistant tumor cells, leading to impaired cross-priming of antigen-specific T lymphocytes. Our findings clarified the detrimental effects of DNA damage signals in chemosensitivity and antitumor immunity, and targeting integrin-αvβ3 has a major implication for treating patient refractory to current anticancer regimens.
Type: article (author version)
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 地主 将久

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