Abstract A55: Uncovering the mechanism of Trib1 in cancer immunotherapy

Abstract T cells provide a fundamental role in cell-mediated immunity, but during chronic antigen exposure such as in the case of cancer, T cells begin to lose effector function and undergo exhaustion. Our goal is to find a target within T cells that could be manipulated to prolong T-cell function and reduce tumor growth. Initial experiments focused on the pseudokinase Trib1, as data suggest that Trib1 acts as a negative regulator of T-cell activation. T cells isolated from mice in which Trib1 was specifically ablated within the T-cell compartment produced more IL-2 compared to wild-type T cells. T cells lacking Trib1 also proliferated more than wild-type T cells. In mice lacking Trib1 in grafted tumor models, tumor growth was reduced. These observations suggest that Trib1 restricts T-cell activation and function. Trib1 is a pseudokinase that is thought to act as a scaffolding molecule to facilitate protein interactions. To understand the mechanism by which Trib1 regulates T-cell function, we performed a proteomic screen to identify interacting partners. The screen was performed in Jurkat cells, an immortalized human T-cell line, expressing a FLAG/strep tagged Trib1. A FLAG pulldown was performed to isolate Trib1, and interacting partners were identified by mass spectrometry. The screen revealed two interacting partners: RFWD2, an E3 ubiquitin ligase also known as COP1, and DET1, a binding partner of COP1. These results provide evidence that Trib1 interacts with COP1 in T cells and suggest that this interaction might be important in the regulation of T-cell function and the regression of tumor growth. Note:This abstract was not presented at the conference. Citation Format: Franklin Iheanacho, Sarah J. Stein, Kelly S. Rome, Martha S. Jordan, Warren S. Pear. Uncovering the mechanism of Trib1 in cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A55.