Breaking Tolerance to Induce Tumor-Specific Cytotoxic CD4 Th1 Cells

描述(由申请人提供)：细胞毒性的CD4Th1细胞正在成为一种生理相关和治疗有用的T细胞谱系，可以成功地靶向肿瘤。到目前为止，对它们分化的细胞和分子途径还知之甚少。我们的初步数据表明，CD134(OX40)共刺激可诱导原始的自身反应性CD4T细胞分化为细胞毒性Th1效应细胞，而CD137(4-1BB)共刺激可最大限度地促进其克隆性增殖。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eome计划是否具有骨记忆潜力。如果是这样的话，这将有助于解决关于CD4T细胞记忆的存在和基础的反复出现的争议。也许我们最意想不到的观察是，CD134+CD137双重共刺激程序抗原特异性细胞毒CD4Th1细胞通过具有相似功能的T细胞来“印记”抗原未经历过的T细胞。我们将测试这些多克隆旁观者是否- 激活的效应器可以被用来靶向抗原丢失的变异型肿瘤细胞，这些肿瘤细胞具有由免疫治疗诱导的特定细胞毒性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。综上所述，拟议的实验将机械地剖析CD134+CD137双重共刺激如何诱导特定和旁观者细胞毒性的CD4 Th1细胞，并开发治疗策略，以利用它们的潜力来控制肿瘤生长，可转化为临床用于治疗人类癌症患者。 与公共卫生相关：细胞毒性的CD4Th1细胞正在成为一种治疗有用的T细胞谱系，可以靶向肿瘤，但到目前为止，对它们分化的途径还知之甚少。我们的初步发现显示，CD134(OX40)+CD137(4-1BB)共刺激通路可诱导细胞毒性的CD4Th1细胞分化，这项工作将研究其潜在机制，并开发临床可翻译的策略，使用双重共刺激来根除肿瘤。

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.