High dose radiation therapy to direct immune responses to pancreatic cancer

项目总结 这一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 是通过放射治疗和免疫治疗控制肿瘤的必要条件和充分条件。我们展示了 在免疫原性低的肿瘤中，肿瘤引流淋巴结中的交叉呈递树突状细胞可能是 在肿瘤控制方面没有明显作用。在这些模型中，放射和免疫疗法是有效的 局部控制的手段，但不能产生新的系统免疫。这项建议的目的是理解 放射如何与肿瘤驻留T细胞相互作用进行局部控制，以及如何恢复肿瘤的交叉呈现 肿瘤相关抗原产生新的全身性抗肿瘤免疫反应。我们假设 放射治疗的内源性疫苗在免疫原性低的肿瘤中的作用有限，目前的成功 依赖于增强先前存在的抗肿瘤免疫。这项研究的具体目的是：1.测试 假设在存在预先存在的免疫的情况下，通过放射治疗和 免疫治疗的发生与交叉呈现和新的免疫反应无关；2：检验假设 缺乏DC交叉呈递限制了放射治疗启动新的系统抗肿瘤的能力。 免疫反应；3：检验抗原提呈和交叉提呈树突状细胞调节的假设 可以使用基因分析来评估患者肿瘤的情况。我们的研究设计结合了CT引导的放射治疗 治疗和结果在多种肿瘤模型中得到验证，包括那些来自基因工程的肿瘤模型 自发模型，使用一定范围的RT剂量和分割。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，使我们能够评估渗透的免疫细胞和抗原呈递 在病人的肿瘤中。这些被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 对病人的观察。

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.