Elucidating the roles of PIK3IP1/TrIP in PI3-kinase regulation, T cell differentiation and T cell function in vivo

Abstract

Abstract Background: The cell surface protein TrIP (Transmembrane Inhibitor of PI3K, gene name: Pik3ip1) functions to downregulate PI3K signaling in T cells and can act as a negative regulator of T cell immune responses. This negative immune regulation was recently reported to promote anti-tumor immunity, implicating TrIP as a potential immunotherapy target. Additionally, TrIP was shown to regulate Th1 vs. Th17 cell fate decisions, suggesting a role in Th17-driven autoimmune disease. Methods: Using a conditional TrIP knockout mouse model we developed, we have begun to interrogate how TrIP expression regulates the effector function of CD8+ T cells and its impact on tumor immune landscape and overall tumor burden. In parallel, we have assessed the effects of TrIP conditional knockout in T cells on progression of experimental autoimmune encephalomyelitis (EAE) in vivo, and also analyzed the effects on Th17 skewing in vitro. Results: We have found that TrIP knockout in CD8+ T cells leads to lower tumor burden compared to WT counterparts. We have also found that the absence of TrIP expression in T cells leads to lower clinical scores and slower disease progression of EAE. Conclusions/Future Directions: We describe preliminary data showing that the absence of TrIP expression on CD8 T cells promotes anti-tumor immunity and have begun to explore its effects on the tumor microenvironment. Expanding on this work, we are developing a P14-transgenic TCR system for use with gp33-expressing tumor lines to investigate potential differences in T cell trafficking to the tumor. Our preliminary data also demonstrates that TrIP knockout T cells lead to a resistance to EAE, prompting further exploration of the role of TrIP in this disease model and in multiple sclerosis.