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

阐明 PIK3IP1/TrIP 对癌症中不同 T 细胞亚群的调节作用

基本信息

批准号：
10387113
负责人：
Benjamin Murter
金额：
$ 4.68万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10387113
关键词：
Address Affect Antigens Antitumor Response B-Cell Activation Binding Biological Biological Response Modifiers Biology CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Proliferation Cell Surface Proteins Cell membrane Cells Complex Data Down-Regulation Exhibits Frequencies Future Gene Expression Genes Growth Growth Factor Harvest Homing Immune Immune response Immunotherapeutic agent Immunotherapy In Vitro Individual Infiltration Inflammatory Inflammatory Response Integral Membrane Protein Knock-out Knockout Mice Kringles Lead Ligation Listeria Lymphoid Malignant Neoplasms Mediating Memory Metabolic Metabolism Modeling Mus Mutation Names PTEN gene Pathway interactions Patients Pattern Phase Phenotype Phosphatidylinositols Phosphotransferases Play Population Positioning Attribute Proteins Regulation Reporting Resistance Rest Role Signal Pathway Signal Transduction T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Tumor Immunity Tumor-infiltrating immune cells Work base cancer immunotherapy cell type cytokine effector T cell experimental study extracellular improved in vivo inhibitor lymph nodes metabolic profile novel receptor recruit response src Homology Region 2 Domain tool trafficking tumor tumor growth tumor microenvironment

项目摘要

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.

项目摘要涉及磷酸肌醇3-激酶（PI3K）的信号通路是高度保守的，严格调节影响所有细胞类型的激活，增殖和存活。 PI3K信号在T细胞中起主要作用抗原由于其直接下游T细胞受体（TCR）/CD28连接而产生的响应。我们的实验室有最近表明，细胞表面蛋白Trip（PI3K的跨膜抑制剂，基因名称：PIK3IP1）具有 T细胞上明显高表达，并且能够下调CD4+ T细胞中的PI3K信号传导，充当 T细胞免疫反应的负调节剂。这些研究表明CD4+ T细胞缺乏TRIP 与WT对照在体内和体外相比，表达表现出更多的Th1炎症表型。这些数据导致我们提出跳闸限制了CD8+ T细胞的炎症活性，并且靶向/敲除该负调节剂可能会促进抗肿瘤免疫。我已经获得了初步数据表明CD8+ T细胞特异性跳闸敲除小鼠（TRIPFL/FLE8ICRE）对生长有抵抗力合成肿瘤。除了增加肿瘤耐药性外，我们还发现与WT同行相比，我们的TripFL/Fle8icre敲除小鼠的浸润T细胞含有两倍。我们还发现CD8+ T细胞是T细胞浸润增加的主要驱动因素，因为它们的频率为 CD4+人群的两倍。这些初步数据是我们的提案的基础阐明CD8+ T细胞中跳闸活性的细胞中性作用，包括其对抗肿瘤免疫的影响。这些研究不仅会提高我们对旅行作为负面免疫调节剂的理解，而且还将告知我们作为未来免疫治疗目标的旅行潜力。