ATM-Mediated DNA Damage Signals Mediate Immune Escape through Integrin-alpha v beta 3-Dependent Mechanisms

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

来源：Cancer Research, 2012, 72(1): 56-65.

DOI：10.1158/0008-5472.CAN-11-2028

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-alpha v beta 3-dependent manner. Integrin-alpha v beta 3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NF kappa B-mediated pathways. Inhibiting tumor-specific expression of integrin-alpha v beta 3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-alpha v beta 3 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-alpha v beta 3 targeting may benefit patients%26apos; refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape. Cancer Res; 72( 1); 56-65.

• 出版日期2012-1-1
• 单位河北医科大学