Breaking Tolerance to Induce Tumor-Specific Cytotoxic CD4 Th1 Cells

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。 公共卫生相关性：细胞毒性CD 4 Th 1细胞正在成为一种治疗上有用的T细胞谱系，可以靶向肿瘤，但到目前为止，对编程其分化的途径知之甚少。我们的初步研究结果表明，CD 134（OX 40）+CD 137（4-1BB）共刺激途径诱导细胞毒性CD 4 Th 1细胞分化，拟议的工作将研究潜在的机制，以及开发临床上可翻译的策略，使用双重共刺激消除肿瘤。

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. PUBLIC HEALTH RELEVANCE: Cytotoxic CD4 Th1 cells are emerging as a therapeutically useful T cell lineage that can target tumors, but up till now the pathways that program their differentiation have been poorly understood. Our preliminary findings reveal that the CD134 (OX40) plus CD137 (4-1BB) costimulatory pathways induce cytotoxic CD4 Th1 cell differentiation, and the proposed work will study the underlying mechanisms as well as develop clinically translatable strategies for using dual costimulation to eradicate tumors.