| First Author | Jinushi M | Year | 2012 |
| Journal | Cancer Res | Volume | 72 |
| Issue | 1 | Pages | 56-65 |
| PubMed ID | 22094875 | Mgi Jnum | J:181026 |
| Mgi Id | MGI:5308662 | Doi | 10.1158/0008-5472.CAN-11-2028 |
| Citation | Jinushi M, et al. (2012) ATM-mediated DNA damage signals mediate immune escape through integrin-alphavbeta3-dependent mechanisms. Cancer Res 72(1):56-65 |
| abstractText | 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-alphavbeta3-dependent manner. Integrin-alphavbeta3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NFkappaB-mediated pathways. Inhibiting tumor-specific expression of integrin-alphavbeta3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-alphavbeta3 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-alphavbeta3 targeting may benefit patients' refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape. |
