Enhancing Anti-Breast Cancer Immunity by Blocking Death Receptor DR5

摘要

As described in the 2008 progress report, the revised hypothesis is that agonist DR5 Ab induced by DNA vaccination will trigger tumor cell apoptosis without compromising T cell activity. The specific aims are to (1)Construct and test DR5 vaccines to induce anti-DR5 Ab, (2) Test the agonist activity of vaccine-induced anti-DR5 Ab, and (3) Amplify anti-tumor activity of DR5 vaccination with novel chemotherapeutics. During the funding period, we established that immune sera to human DR5 exhibit agonist activity to induce apoptosis in triple negative breast cancer cells and to inhibit tumor growth in vivo. To enable the testing of human DR5 vaccine in tolerant hosts, hDR5 transgenic mice have been generated and they are being back-crossed into BALB/c background. These mice will continue to be useful for studies targeting hDR5. To test the principle of inducing greater immunity with heterologous DR5 DNA vaccine, we have cloned DR5 cDNA from rat and two species of wild mice. These new reagents can be tested in future studies. To complement DR5 vaccination with additional therapies, we showed Sp-1 mediated TRAIL induction by HDAC inhibitor and that Akt survival pathway contributes to TRAIL resistance. These findings provide strong basis for combining DR5 vaccination with targeted therapy.