Elucidating The Roles of PIK3IP1/TrIP Regulation on Distinct T Cell Subsets in the Context of Cancer

项目摘要 磷脂酰肌醇-3-激酶（PI 3 Ks）信号通路是一种高度保守和严格调控的信号通路 影响所有细胞类型的活化、增殖和存活。PI 3 K信号在T细胞中起着重要作用 由于其位置直接位于T细胞受体（TCR）/CD 28连接的下游，因此对抗原产生应答。我们的实验室 最近显示，细胞表面蛋白TrIP（PI 3 K的跨膜抑制剂，基因名称：Pik 3 ip 1）具有与细胞表面蛋白TrIP（PI 3 K的跨膜抑制剂，基因名称：Pik 3 ip 1）相同的生物学活性。 在T细胞上明显高表达，并且能够下调CD 4 + T细胞中的PI 3 K信号传导， T细胞免疫反应的负调节因子。这些研究表明，缺乏TrIP的CD 4 + T细胞 在体内和体外，与WT对照相比，表达的小鼠表现出更多的Th 1炎性表型。这些 数据使我们提出TrIP限制了CD 8 + T细胞的炎症活性， 靶向/敲除该负调节因子可以促进抗肿瘤免疫。我已经得到 初步数据表明，CD 8 + T细胞特异性TrIP敲除小鼠（TrIPf 1/flE 8icre）对生长有抗性， 同基因肿瘤除了增加的肿瘤抵抗力，我们还发现， 我们的TrIPf 1/f1 E8 icre敲除小鼠含有的浸润性T细胞是其WT对应物的两倍。我们 还发现CD 8 + T细胞是这种增加的T细胞浸润的主要驱动力，因为它们的频率是 是CD 4+细胞的两倍。这些初步数据是我们旨在进一步 阐明TrIP活性在CD 8 + T细胞中的细胞内在效应，包括其对抗肿瘤免疫的影响。这些 这些研究不仅将提高我们对TrIP作为负性免疫调节剂的理解，而且还将提供有关 TrIP作为未来免疫靶点的潜力。

PROJECT SUMMARY 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. Our lab has recently 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 downregulating PI3K signaling in CD4+ T cells, acting as a negative regulator of T cell immune responses. These studies revealed that CD4+ T cells lacking TrIP expression exhibit a more Th1 inflammatory phenotype compared to WT controls both in vivo and in vitro. These data have led us to propose that TrIP restricts the inflammatory activity of CD8+ T cells, and that targeting/knockout of this negative regulator may promote anti-tumor immunity. I have already obtained preliminary data demonstrating that CD8+ T cell-specific TrIP knockout mice (TrIPfl/flE8icre) are resistant to growth of syngeneic tumors. In addition to increased tumor resistance, we have also found that tumors harvested from our TrIPfl/flE8icre knockout mice contain twice as many infiltrating T cells compared to their WT counterparts. We also found that CD8+ T cells were the main drivers of this increased T cell infiltration, as their frequency was double that of the CD4+ population. These preliminary data are the basis of our proposal aimed at further elucidating cell-intrinsic effects of TrIP activity in CD8+ T cells, including its impact on antitumor immunity. These studies will not only improve our understanding of TrIP as a negative immune regulator, but also inform on the potential for TrIP as a future immunotherapeutic target.