ATM-mediated DNA damage signals mediate immune escape through integrin-αvß3-dependent mechanisms.
Cancer Res
; 72(1): 56-65, 2012 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-22094875
ABSTRACT
Although the tumor microenvironment plays a critical role in tumor progression and metastasis, the relationship between chemotherapy resistance and modulation of the tumor microenvironment remains unclear. Here, we report a novel mechanism showing how constitutive DNA damage signals in therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvß3-dependent manner. Integrin-αvß3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NFκB-mediated pathways. Inhibiting tumor-specific expression of integrin-αvß3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-αvß3 expression targeted dendritic cells, facilitating their ability to phagocytose viable therapy-resistant tumor cells and thereby impaired their ability to cross-prime antigen-specific T lymphocytes. Together, our results clarify the detrimental effects of constitutive DNA damage signals to chemosensitivity and antitumor immunity. Furthermore, these findings suggest that integrin-αvß3 targeting may benefit patients' refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
Transducción de Señal
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Proteínas Serina-Treonina Quinasas
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Proteínas de Ciclo Celular
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Escape del Tumor
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Proteínas Supresoras de Tumor
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Integrina alfaVbeta3
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Proteínas de Unión al ADN
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Res
Año:
2012
Tipo del documento:
Article
País de afiliación:
Japón