Background The signaling pathways involving phosphoinositide-3-kinases (PI3Ks) are highly conserved and tightly regulated to influence the activation, proliferation, and survival of all cell types. PI3K signaling plays a major role in T cell responses to antigen due to its position directly downstream of T cell receptor (TCR)/CD28 ligation.^{1, 2} Our lab has shown that the cell surface protein TrIP (Transmembrane Inhibitor of PI3K, gene name: Pik3ip1) has a distinctly high expression on T cells and is capable of regulating PI3K signaling in T cells, acting as a negative regulator of T cell immune responses.^{3, 4} These studies revealed that CD4⁺ T cells lacking TrIP expression exhibit a more Th1 inflammatory phenotype compared to WT T cells, both in vivo and in vitro. ³ These data have led us to propose that TrIP restricts the inflammatory activity of T cells, including CD8⁺ T cells, and that targeting/knockout of this negative regulator may promote anti-tumor immunity.

Methods Using a novel conditional TrIP knockout mouse model developed in house, we have performed syngeneic tumor challenges in CD8⁺ T cell-specific TrIP knockout mice (TrIP^fl/flE8i^cre). We have also characterized the tumor immune infiltrate of these mice to understand the impact of T cell-specific TrIP deficiency on the immune landscape.

Results Our data show that CD8⁺ T cell-specific TrIP knockout mice (TrIP^fl/flE8i^cre) are resistant to growth of syngeneic tumors. In addition to increased tumor resistance, we have also found that tumors harvested from our TrIP^fl/flE8i^cre knockout mice contain twice as many infiltrating T cells compared to their WT counterparts. We also found that CD8⁺ T cells are the major drivers of this infiltration, and importantly don’t display any increase in exhaustion.

Conclusions We describe data demonstrating that TrIP, a relatively novel PI3K inhibitor uniquely expressed on the surface of T cells, plays a significant role in the antitumor immune activity of CD8⁺ T cells. Our CD8⁺ T cell-specific TrIP knockout mice are resistant to tumor challenge and show more robust tumor CD8⁺ T cell infiltrate. We are hoping for future/ongoing adoptive transfer experiments will help elucidate if TrIP knockout promotes infiltration/proliferation/survival within the TME. Nevertheless, we propose TrIP as an exciting novel immunotherapeutic target worthy of further investigation.

References

1. Okkenhaug K, Turner M, Gold MR. PI3K Signaling in B Cell and T Cell Biology. Front Immunol 2014;5:557. doi:10.3389/fimmu.2014.00557

2. Kane LP, Weiss A. The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3. Immunol Rev 2003;192:7–20. doi:10.1034/j.1600-065X.2003.00008.x

3. Uche UU, Piccirillo AR, Kataoka S, et al. PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt. J Exp Med. 2018;215:3165–3179. doi:10.1084/jem.20172018

4. DeFrances MC, Debelius DR, Cheng J, Kane LP. Inhibition of T-cell activation by PIK3IP1. Eur J Immunol 2012;42:2754–2759. doi:10.1002/eji.201141653