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

项目总结 涉及磷脂酰肌醇-3-激酶(PI3Ks)的信号通路是高度保守和严格调控的 影响所有类型细胞的激活、增殖和存活。PI3K信号通路在T细胞中的重要作用 由于其位于T细胞受体(TCR)/CD28连接的正下游而对抗原产生应答。我们的实验室有 最近发现，细胞表面蛋白TRIP(PI3K的跨膜抑制因子，基因名称：PIK3IP1)具有 在T细胞上明显高表达，并能够下调CD4+T细胞中的PI3K信号，起到 T细胞免疫反应的负调节因子。这些研究表明，CD4+T细胞缺乏TRIP 在体内和体外，与WT对照组相比，表达显示出更多的Th1炎症表型。这些 数据使我们提出TRIP限制CD8+T细胞的炎症活动，并且 靶向/敲除这种负性调节因子可能会促进抗肿瘤免疫。我已经得到了 初步数据显示CD8+T细胞特异性TRIP基因敲除小鼠(TrIPfl/flE8icre)对生长具有抵抗力 同基因肿瘤。除了增加对肿瘤的耐药性外，我们还发现，从 我们的TrIPfl/flE8icre基因敲除小鼠含有的浸润性T细胞是WT小鼠的两倍。我们 还发现CD8+T细胞是这种T细胞浸润增加的主要驱动因素，因为他们的频率是 是CD4+人群的两倍。这些初步数据是我们建议的基础，旨在进一步 阐明CD8+T细胞TRIP活性的细胞内效应，包括其对抗肿瘤免疫的影响。这些 研究不仅将加深我们对TRIP作为一种负免疫调节剂的理解，而且还将有助于了解 TRIP作为未来免疫治疗靶点的可能性。

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.