High dose radiation therapy to direct immune responses to pancreatic cancer

项目摘要 该提议的关键初步数据是，在临床前模型中，预先存在的肿瘤驻留T细胞 对于通过放射疗法和免疫疗法控制肿瘤来说是必要的和充分的。我们证明 在免疫原性差的肿瘤中，肿瘤引流淋巴结中的交叉呈递树突状细胞可能 在肿瘤控制中没有显著作用。在这些模型中，放射和免疫疗法是有效的 局部控制手段，但未能产生新的全身免疫。本提案的目的是为了了解 辐射如何与肿瘤驻留T细胞相互作用以进行局部控制，以及如何恢复肿瘤的交叉呈递。 肿瘤相关抗原以产生新的全身性抗肿瘤免疫应答。我们假设 放射治疗的内源性疫苗作用在免疫原性差的肿瘤中是有限的，并且目前的成功 依赖于增强已有的抗肿瘤免疫力本研究的具体目的是：1.测试 假设在存在预先存在的免疫力的情况下，通过放射治疗和 免疫治疗的发生独立于交叉呈递和新的免疫应答; 2：检验假设 缺乏DC交叉呈递限制了放射治疗启动新的全身性抗肿瘤的能力， 免疫应答; 3：检验抗原呈递和交叉呈递DC的调节 可以使用遗传分析在患者肿瘤中进行评估。我们的研究设计结合了CT引导放射治疗 治疗和结果在多种肿瘤模型中得到验证，包括来自基因工程的那些 自发模型，使用一系列RT剂量和分次。我们对临床样本的分析使用了高 高质量的生物信息学方法，使我们能够评估浸润的免疫细胞和抗原呈递 在病人的肿瘤中。这些应用于一项独特的临床研究，使我们能够验证我们的临床前 观察患者。

PROJECT SUMMARY The critical preliminary data for this proposal is that in preclinical models, pre-existing tumor-resident T cells are both necessary and sufficient for tumor control by radiation therapy and immunotherapy. We demonstrate that in poorly immunogenic tumors, cross-presenting dendritic cells in the tumor-draining lymph node may be playing no significant role in tumor control. In these models, radiation and immunotherapy are an effective means of local control but fail to engender new systemic immunity. The aim of this proposal is to understand how radiation interacts with tumor resident T cells for local control, and how to restore cross-presentation of tumor-associated antigens to generate new systemic anti-tumor immune responses. We hypothesize that the endogenous vaccine effect of radiation therapy is limited in poorly immunogenic tumors, and current success relies on amplifying pre-existing anti-tumor immunity. The specific aims of this study are to 1: Test the hypothesis that in the presence of pre-existing immunity, tumor control by radiation therapy and immunotherapy occurs independent of cross-presentation and new immune responses; 2: Test the hypothesis that deficient DC cross-presentation limits the ability of radiation therapy to initiate new systemic anti-tumor immune responses; 3: Test the hypothesis that regulation of antigen presentation and cross-presenting DC can be assessed in patient tumors using genetic analysis. Our study design incorporates CT-guided radiation therapy and results are validated in multiple tumor models including those from genetically engineered spontaneous models, using a range of RT doses and fractionations. Our analyses of clinical samples use high quality bioinformatic approaches that allow us to evaluate the infiltrating immune cells and antigen presentation in patient tumors. These are applied to a unique clinical study that allows us to validate our preclinical observations in patients.