Abstract The MYC oncogene has been implicated in the pathogenesis of many types of human cancer. The Felsher laboratory uses a conditional Tet-off MYC mouse model to study the formation of tumors in multiple tissue types, such as lymphoma, and has demonstrated that MYC-induced tumorigenesis is reversible. We have found that many cancers are “oncogene addicted” to MYC. Our laboratory has shown that an adaptive T cell-mediated immune response is essential for sustained tumor regression upon MYC inactivation (Rakhra et al, Cancer Cell, 2010). Now, we have found evidence suggesting that upon MYC inactivation in tumors, B cells are activated and are critical to tumor regression. MYC inactivation in a tumor was associated with the induction of an antibody-mediated response against tumor cells. This humoral response could mediate the killing of tumor cells in an Antibody-Dependent Cellular Cytotoxicity (ADCC) assay. Our work suggests that MYC inactivation results in a B cell-mediated immune response and that ADCC may contribute to tumor regression. Citation Format: Stephanie C. Casey, Rachel K. Do, Dean W. Felsher. The role of the immune system in sustained tumor regression following oncogene inactivation. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B02.