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 CD4 Th1 细胞正在成为一种生理相关且在治疗上有用的 T 细胞谱系，可以成功地靶向肿瘤。到目前为止，我们对细胞和分子途径的分化知之甚少。 CD134 (OX40) 共刺激诱导 na¿ ve 自身反应性 CD4 T 细胞可分化为细胞毒性 Th1 效应细胞，并且添加 CD137 (4-1BB) 共刺激可最大限度地提高其克隆扩增能力，此分化过程需要 IL-2 和 T-box 转录因子 Eomesodermin (Eomes)。该实验计划将测试 Eomes 是否具有真实的记忆潜力，如果是的话，这将有助于解决有关 CD4 T 细胞记忆的存在和基础的反复出现的争议。 CD134 + CD137 双重共刺激程序化抗原特异性细胞毒性 CD4 Th1 细胞“印记”抗原 - 具有类似功能能力的缺乏经验的旁观 T 细胞 我们将测试这些多克隆旁观者是否 - 激活的效应器可用于靶向抗原丢失变异肿瘤细胞，这些肿瘤细胞具有由免疫治疗引起的特定细胞毒性 T 细胞识别的下调表位，并且如果这些旁观者 T 细胞介导与免疫治疗相关的致病副作用。从机制上剖析 CD134 加 CD137 双重共刺激如何诱导特异性和旁观者细胞毒性 CD4 Th1 细胞，并制定治疗策略以利用其控制肿瘤生长的潜力，并可在临床上转化为治疗人类癌症患者。