Breaking Tolerance to Induce Tumor-Specific Cytotoxic CD4 Th1 Cells

描述（由申请人提供）：细胞毒性CD4 Th1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，人们对控制它们分化的细胞和分子途径知之甚少。我们的初步数据表明，CD134 （OX40）共刺激诱导无自我反应性CD4 T细胞分化为细胞毒性Th1效应细胞，CD137 （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）。该实验计划将测试Eomes程序是否具有骨性记忆潜力。如果是这样，这将有助于解决关于CD4 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结果是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-没有经验的具有相似功能能力的备用T细胞。我们将测试这些多克隆旁观者

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.