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

• 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
• 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

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类记忆 T 细胞无法对 T 细胞受体 (TCR) 的刺激做出反应。这种免疫抑制表现为 NF-κB 和 NFAT 激活、IFN-α 的减少。产生和细胞增殖响应 T 细胞受体 (TCR) 的刺激。去除肿瘤腹水后对肿瘤相关 T 细胞 (TAT) 进行分析，肿瘤相关 T 细胞 (TAT) 的无反应性很快就会逆转。通过以剂量依赖性方式添加无细胞肿瘤腹水，可以很容易地重新建立 TAT 的无反应性。新的初步数据表明，从腹水中分离出的两种极性脂质磷脂酰丝氨酸 (PS) 和 GD3 神经节苷脂 (GD3) 会在 PLC 处或附近诱导 TCR 信号传导阻滞？在 TAT 中。我们的长期目标是（1）检验以下假设：人类卵巢肿瘤微环境中存在的脂质会导致无反应性和 TAT 无法控制肿瘤进展，以及（2）通过阻断极性脂质的免疫抑制活性，T 细胞将重新激活并介导原位肿瘤杀伤。 Ai 1 重点关注肿瘤腹水（或腹水中存在的两种免疫抑制极性脂质）是否直接作用于 T 细胞以诱导 TCR 信号传导停滞，或者这种停滞是否由与极性脂质结合并被极性脂质激活的细胞间接介导。第一个目标将为消除或功能性阻断免疫抑制脂质和/或脂质结合细胞的方案设计提供初步原理。我们预测并将在目标 2 中进行测试，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 细胞的无反应性，防止诱导进入肿瘤的功能性 T 细胞的 TCR 信号传导阻滞，并将导致 T 细胞杀死异种移植物中的肿瘤细胞。他的目标取决于 PI 设计的新型异种移植模型，该模型首次使得量化和监测肿瘤内 T 细胞功能以及量化肿瘤细胞数量的变化成为可能。在最终目标中，提出了从肿瘤腹水中分离出的两种极性脂质（PS 和 GD3）的结构/功能研究。这些研究有望进一步深入了解脂质诱导的 TCR 信号传导阻滞的分子机制，并设计出靶向和阻断每个分子抑制功能所需的特定分子结构的新方法。 我们拟议研究的成功得益于 PI 组建的合作研究团队中的多元化专业知识（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治疗）。