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

Jinushi Masahisa; Chiba Shigeki; Baghdadi Muhammad; Kinoshita Ichiro; Dosaka-Akita Hirotoshi; Ito Koyu; Yoshiyama Hironori; Yagita Hideo; Uede Toshimitsu; Takaoka Akinori

Title	en ATM-Mediated DNA Damage Signals Mediate Immune Escape through Integrin-αvβ3-Dependent Mechanisms
Creator	en Jinushi, Masahisa en Chiba, Shigeki en Baghdadi, Muhammad en Kinoshita, Ichiro NRID 1000040343008 en Dosaka-Akita, Hirotoshi en Ito, Koyu en Yoshiyama, Hironori NRID 1000010253147 en Yagita, Hideo en Uede, Toshimitsu NRID 1000000160185 en Takaoka, Akinori NRID 1000030323611
Accessrights	open access
Subject	Other ja Integrin-αvβ3 Other en Chemoresistance Other en DNA damage response Other en Antitumor immunity Other en Phagocytosis NDC 493
Description	Abstract en 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.
Publisher	en American Association for Cancer Research
Date	Issued2012-01-01
Language	eng
Resource Type	journal article
Version Type	AM
Identifier	HDL http://hdl.handle.net/2115/51015
Relation	isVersionOf DOI https://doi.org/10.1158/0008-5472.CAN-11-2028 PMID 22094875
Journal	PISSN 0008-5472 en Cancer Research Volume Number72 Issue Number1 Page Start56 Page End65
File	fulltext CR72-1_56-65.pdf 2.24 MB (application/pdf) Issued2012-01-01 fulltext Supplementary_Data.pdf 998.96 KB (application/pdf) Issued2012-01-01
Oaidate	2023-07-26