Re-activating Memory T Cells in the Microenvironment of Human Tumors

重新激活人类肿瘤微环境中的记忆 T 细胞

基本信息

批准号：
8723760
负责人：
RICHARD B BANKERT
金额：
$ 31.9万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-20 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723760
关键词：
Address Animal Model Ascites Binding Biological Assay Biophysics CD8B1 gene Cancer Patient Cell Count Cell Proliferation Cell physiology Cells Characteristics Clinical Data Dose Excision Failure G(M3) Ganglioside Ganglioside GD3 Gangliosides Genetic Glycosphingolipids Goals Human Immune response Immunology Immunosuppression Immunosuppressive Agents In Situ Infiltration Interferons Lead Lecithin Length Link Lipid Binding Lipid Biochemistry Lipids Liquid substance Lung Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Mediating Membrane Methods Molecular Molecular Structure Monitor Mus Neoplasm Metastasis Omentum Patients Phosphatidylserines Phospholipids Prevention Production Proliferating Protocols documentation Receptor Signaling Research Signal Transduction Signaling Molecule Stromal Cells Stromal Neoplasm Structure T cell anergy T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Time Tumor Cell Biology Xenograft Model Xenograft procedure anergy cancer immunotherapy cell killing cytokine design in vivo insight killings model design neoplastic cell novel ovarian neoplasm prevent public health relevance response restoration sialylation success tumor tumor eradication tumor microenvironment tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Human memory T cells present in ovarian tumor ascites fluids fail to respond to stimulation via the T cell receptor (TCR). This immunosuppression is manifest by decreases in NF-?B and NFAT activation, IFN-? production, and cell proliferation in response to stimulation via the T cell receptor (TCR). The non-responsiveness of the tumor-associated T cells (TAT) is quickly reversed when the cells are assayed after the removal of the tumor ascites fluid. The anergy of the TAT is easily re-established by the addition of cell free tumor ascites fluid in a dose dependent fashion. New preliminary data have established that two polar lipids phosphatidylserine (PS) and GD3 ganglioside (GD3), isolated from the ascites fluids, induce a TCR signaling arrest at or just proximal to PLC? in the TAT. Our long term goals are (1) to test the hypothesis that lipids present within human ovarian tumor microenvironments contribute to the anergy and to the failure of TAT to control tumor progression, and (2) that by blocking the immunosuppressive activity of the polar lipids T cells will become re-activated and mediate tumor killing in situ. Ai 1 focuses on whether the tumor ascites fluid, (or the two immunosuppressive polar lipids present in the ascites fluid), act directly on the T cells to induce the TCR signaling arrest or whether ths arrest is mediated indirectly by cells that bind to and are activated by the polar lipids. This firt aim will provide an initial rationale for the design of protocols to eliminate or functionally bloc the immunosuppressive lipids and/or lipid binding cells. We predict and will test in Aim 2 that blocking the lipid immunomodulatory effects will reverse the anergy of T cells present within an ovarian tumor microenvironment, prevent the induction of the TCR signaling arrest of functional T cells that enter the tumor, and will result in a T cell killing of tumor cells in the xenograft. his aim is dependent upon a novel xenograft model designed by the PI that has made it possible for the first time to quantify and monitor intratumoral T cell function and to quantify changes in tumor cell numbers. In the final aim structure/function studies of the two polar lipids (PS and GD3) isolated from the tumor ascites fluids are proposed. These studies are expected to provide further insights into the molecular mechanisms of the lipid-induced TCR signaling arrest, and to lead to the design of novel methods that target and block specific molecular structures that are found to be required for each molecule's inhibitory function. The success of our proposed studies is enhanced by the diverse expertise (including immunology, tumor cell biology, lipid biochemistry, genetics, animal modeling, membrane biophysics and clinical cancer immunotherapy) present within our collaborative research team that has been assembled by the PI.

描述（由申请人提供）：卵巢肿瘤腹水中存在的人记忆T细胞无法通过T细胞受体（TCR）对刺激做出反应。这种免疫抑制是通过nf-？b和nFAT激活的降低而表现出来的，ifn-？通过T细胞受体（TCR）刺激响应刺激的生产和细胞增殖。去除肿瘤腹水液体后测定细胞时，肿瘤相关T细胞（TAT）的无反应性很快就会逆转。通过以剂量依赖性的方式添加无细胞的腹水腹水流体，很容易重新建立TAT的消极。新的初步数据已经确定，从腹水液中分离出来的两种极性脂质磷脂酰丝氨酸（PS）和GD3神经节苷脂（GD3），在PLC上诱导TCR信号停滞，或者与PLC近端诱导？在tat中。我们的长期目标是测试以下假设：人类卵巢肿瘤微环境中存在的脂质有助于反应和TAT无法控制肿瘤进展的失败，并且（2）通过阻止极性脂质T细胞的免疫抑制活性T细胞会重新激活并促进杀死肿胀的肿瘤。 AI 1的重点是肿瘤腹水液（或腹水液中存在的两种免疫抑制极性脂质）直接作用于T细胞，以诱导TCR信号停滞，还是由与极性脂质结合并激活的细胞间接介导。该FIRT AIM将为设计方案设计以消除或在功能功能上集结免疫抑制脂质和/或脂质结合细胞的初始基本原理。我们预测并将在AIM 2中测试，阻断脂质免疫调节作用将逆转卵巢肿瘤微环境中存在的T细胞的反应，以防止诱导进入肿瘤的功能性T细胞的TCR信号传导停滞，并导致Xenogograft中肿瘤细胞的T细胞杀死T细胞。他的目的取决于PI设计的新型异种移植模型，该模型首次可以量化和监测肿瘤内T细胞功能并量化肿瘤细胞数量的变化。在最终的目标结构/功能研究中，提出了从肿瘤腹水流体分离的两种极性脂质（PS和GD3）的研究。这些研究有望提供进一步的见解，以了解脂质诱导的TCR信号停滞的分子机制，并导致设计新方法的设计，这些方法靶向和阻断每个分子抑制功能所需的特定分子结构。我们提出的研究的成功得到了多样化的专业知识（包括免疫学，肿瘤细胞生物学，脂质生物化学，遗传学，动物建模，膜生物物理学和临床癌症免疫疗法）的成功，这是我们的协作研究团队中由PI组装而成的。