| First Author | Liao D | Year | 2011 |
| Journal | Cancer Res | Volume | 71 |
| Issue | 17 | Pages | 5688-96 |
| PubMed ID | 21784871 | Mgi Jnum | J:175779 |
| Mgi Id | MGI:5287313 | Doi | 10.1158/0008-5472.CAN-11-1264 |
| Citation | Liao D, et al. (2011) Targeted Therapeutic Remodeling of the Tumor Microenvironment Improves an HER-2 DNA Vaccine and Prevents Recurrence in a Murine Breast Cancer Model. Cancer Res 71(17):5688-96 |
| abstractText | The tumor microenvironment (TME) mediates immunosuppression resulting in tumor cell escape from immune surveillance and cancer vaccine failure. Immunosuppression is mediated by the STAT-3 transcription factor, which potentiates signaling in tumor and immune cells. Because immunosuppression continues to be a major inhibitor of cancer vaccine efficacy, we examined in this study whether therapeutically targeted delivery of a synthetic STAT-3 inhibitor to the TME, combined with an HER-2 DNA vaccine can improve immune surveillance against HER-2(+) breast cancer and prevent its recurrence. To this end, we developed a novel ligand-targeted nanoparticle (NP) encapsulating a CDDO-Im payload capable of specific delivery to the TME, which showed an effective therapeutic inhibition of STAT-3 activation in primary tumors. Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells. These changes correlated with delayed growth of orthotopic 4TO7 breast tumors and, when combined with an HER-2 DNA vaccine, prevented HER-2(+) primary tumor recurrence in immunocompetent mice. Furthermore, antitumor T-cell responses were enhanced in splenocytes isolated from mice treated with this combination therapy. Together, these data show effective protection from cancer recurrence through improved immune surveillance against a tumor-specific antigen. Cancer Res; 71(17); 5688-96. (c)2011 AACR. |
