Visualizing radiation-induced tumor immune responses

项目总结/摘要 毫无疑问，检查点阻断和过继性T细胞转移的显著成功是由于免疫缺陷综合征的发生。 临床已经将免疫疗法牢固地定位为癌症治疗的第四大支柱，仅次于手术， 放射治疗和化学治疗，创造了同等程度的机会和挑战。一些 我们面临的最紧迫的问题包括：1）相对有限的回应率，2） 免疫相关的副作用，以及3）缺乏预测性生物标志物。当结合免疫疗法时， 尽管各种模式将解决其中一些挑战，但新的挑战可能会出现。当然，辐射 联合免疫疗法可以产生有希望的反应，但我们对免疫疗法的理解是， 所涉及的机制非常有限。也许放射治疗最引人注目的方面在于它的 细胞毒性性质和其产生免疫原性肿瘤细胞死亡中心的能力，其特征在于 独特的生物标志物特征，最显著的是钙网蛋白的细胞表面暴露。树突状细胞具有 这种特殊的能力可以感知危险信号，并通过免疫系统的自适应臂将它们传递给免疫系统。 允许细胞毒性CD 8 T细胞寻找目标并杀死它们。重要的是要明白， 当它没有发生时，如果它转化为系统免疫力和战斗能力， 微转移性疾病然而，我们解决这些问题的工具完全不够。这确 该提案旨在开发强大的新工具，使我们能够通过以下方式询问肿瘤-宿主界面： 使用工程抗体片段在主动免疫应答期间对免疫细胞进行非侵入性成像 免疫PET将开发一种新型钙网蛋白免疫PET探针，并与 现有的CD 8免疫PET探针评估诱导免疫原性细胞死亡的能力， 效应细胞的流入和扩增。目的是证明CD 8免疫PET可用于监测 放射治疗期间的肿瘤免疫反应;钙网蛋白免疫PET可以提供早期非肿瘤免疫反应。 免疫原性细胞死亡侵袭性生物标志物和预测肿瘤中随后的CD 8 T细胞浸润， 钙网蛋白和CD 8成像的组合可用于优化RT剂量/分级时间表， 来创造免疫治疗的最佳辅助剂。

PROJECT SUMMARY / ABSTRACT There is no doubt that the remarkable success of checkpoint blockade and of adoptive T cell transfer in the clinic has positioned immunotherapy firmly as the fourth pillar of cancer treatment, next to surgery, radiotherapy, and chemotherapy and created opportunities and challenges in equal measures. Some of the most pressing questions we are facing include 1) relatively limited response rates, 2) the emergence of immune-related side effects, and 3) a lack of predictive biomarkers. While combining immunotherapies, within and across modalities will address some of these challenges, new ones are likely to arise. Certainly, radiation therapy combined with immunotherapy can yield promising responses, but our understanding of the mechanisms involved is very limited. Perhaps the most compelling aspect of radiation therapy lies in its cytotoxic nature and its ability to create a hub of immunogenic tumor cell death which is characterized by a unique biomarker signature, most notably cell surface exposure of calreticulin. Dendritic cells have the exceptional ability to sense danger signals and relay them to the adaptive arm of the immune system by way of licensing cytotoxic CD8 T to seek out their target and kill. The important issue is to understand when this happens, when it doesn't happen and if it translates into systemic immunity and the ability to fight micrometastatic disease. However, our tools to address these questions are totally inadequate. Indeed, this proposal aims to develop powerful new tools that allow us to interrogate the tumor-host interface by noninvasively imaging immune cells during an active immune response using engineered antibody fragments and immunoPET. A novel calreticulin immunoPET probe will be developed, and evaluated alongside an existing CD8 immunoPET probe for the ability to assess the induction of immunogenic cell death and the influx and expansion of effector cells. The goal is to demonstrate that CD8 immunoPET can be used to monitor tumor immune responses during radiation therapy; that calreticulin immunoPET can provide an early non- invasive biomarker of immunogenic cell death and predict subsequent CD8 T cell infiltration in tumors, and that the combination of calreticulin and CD8 imaging can be used to optimize RT dose/fractionation schedules so as to create the optimal adjuvant to immunotherapy.