Breaking Tolerance to Induce Tumor-Specific Cytotoxic CD4 Th1 Cells

打破耐受性以诱导肿瘤特异性细胞毒性 CD4 Th1 细胞

• 批准号: 8785648
• 负责人: ADAM J ADLER
• 金额: $ 37.93万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785648
• 关键词: Activities of Daily Living; Adverse effects; Antigen Targeting; Antigens; Boxing; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cell Differentiation process; Cell Lineage; Cells; Clonal Expansion; Cytotoxic T-Lymphocytes; Data; Development; Epitopes; Growth; Human; Immunotherapy; Interleukin-2; MHC Class II Genes; Mediating; Memory; Molecular; Natural Killer Cells; Pathway interactions; Principal Investigator; Process; Role; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Time; Translating; Tumor Immunity; Variant; Work; base; bone; cytotoxic; defined contribution; experience; imprint; memory CD4 T lymphocyte; neoplastic cell; programs; research study; response; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Cytotoxic CD4 Th1 cells are emerging as a physiologically relevant and therapeutically useful T cell lineage that can successfully target tumors. Until now the cellular and molecular pathways that program their differentiation have been poorly understood. Our preliminary data demonstrates that CD134 (OX40) costimulation induces na¿ve self-reactive CD4 T cells to differentiate into cytotoxic Th1 effectors, and the addition of CD137 (4-1BB) costimulation maximizes their clonal expansion. This differentiation process requires IL-2, and the T-box transcription factor Eomesodermin (Eomes). The experimental plan will test if Eomes programs bone fide memory potential. If so, this will help to resolve the recurring controversy regarding the existence and basis of CD4 T cell memory. Perhaps our most unexpected observation is that CD134 plus CD137 dual costimulation-programmed antigen-specific cytotoxic CD4 Th1 cells "imprint" antigen - inexperienced bystanding T cells with similar functional capacities. We will test if these polyclonal bystander - activated effectors can be exploited to target antigen-loss variant tumor cells that have down-regulated epitopes recognized by specific cytotoxic T cells elicited by immunotherapy, and if these bystander T cells mediate pathogenic side effects associated with immunotherapy. In summary, the proposed experiments will mechanistically dissect how CD134 plus CD137 dual costimulation induces specific and bystander cytotoxic CD4 Th1 cells, and develop therapeutic strategies to harness their potential to control tumor growth that can be translated clinically to treat human cancer patients.

描述（由申请人提供）：细胞毒性CD 4 Th 1细胞正在成为一种生理学相关和治疗上有用的T细胞谱系，可以成功靶向肿瘤。到目前为止，对编程其分化的细胞和分子途径知之甚少。我们的初步数据表明，CD 134（OX 40）共刺激诱导幼稚自身反应性CD 4 T细胞分化为细胞毒性Th 1效应细胞，加入CD 137（4-1BB）共刺激使其克隆扩增最大化。这种分化过程需要IL-2和T-box转录因子Eomesodermin（Eomes）。实验计划将测试Eomes是否编程真正的记忆潜力。如果是这样的话，这将有助于解决关于CD 4 T细胞记忆的存在和基础的反复争论。也许我们最意想不到的观察是，CD 134加上CD 137双重共刺激程序化的抗原特异性细胞毒性CD 4 Th 1细胞“印记”抗原-无经验的旁观者T细胞具有相似的功能能力。我们将测试这些多克隆的旁观者- 激活的效应物可用于靶向抗原丢失变体肿瘤细胞，所述肿瘤细胞具有由免疫疗法引发的特异性细胞毒性T细胞识别的下调表位，并且如果这些旁观者T细胞介导与免疫疗法相关的致病性副作用。总之，拟议的实验将机械解剖如何CD 134加上CD 137双共刺激诱导特异性和旁观者细胞毒性CD 4 Th 1细胞，并开发治疗策略，利用其潜力来控制肿瘤生长，可以转化为临床治疗人类癌症患者。