Studies have been performed to demonstrate that effectors of enzymes of the ubiquitin proteasome pathway associated with T cell activation are able to impair tumor survival by abrogating the immune evasion mechanism. Immune evasion is a collective term for the various strategies employed by tumors to suppress the host immune system's ability to recognize and destroy cancer cells. Significant advances in the understanding of the mechanisms of cancer immune evasion have led to the successful development of biologic immunotherapies that showed clinical efficacy against hematological as well as solid tumors. These include monoclonal antibodies, allogeneic hematopoietic stem cell transplantation, vaccination, cytokines, T cell checkpoint blockade and adoptive transfer of engineered T cells. Owing to the multifaceted nature of cancer immune evasion, however, several different approaches will likely be necessary for effective therapeutic management. We have adopted a dual targeting approach focused on the ubiquitin proteasome pathway to develop novel small molecule cancer immunotherapies. Using the UbiProTM discovery platform, we have identified inhibitors of a deubiquitylase (DUB) that is highly expressed in regulatory T cells (Tregs) and plays a critical role in promoting Treg functions. These inhibitors are shown to suppress Treg functions and promote T-effector cell function ex vivo and in vivo. In addition, we have identified inhibitors of an E3 ubiquitin ligase that negatively regulates T-effector cell function. These inhibitors are shown to activate T-cells and NK cell functions in vitro. A combination of such inhibitors should provide powerful anti-cancer immunotherapy.
Citation Format: Suresh Kumar, Liqing Wang, Jian Wu, Feng Wang, Saket Agarwal, Matthew Kodrasov, Wayne Hancock, Michael Mattern. Targeting the ubiquitin signaling system for cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B007.
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