Radiotherapy-induced tumor immunity

 描述（由申请人提供）：癌症放射治疗具有全身性后果，其通过受照射组织和肿瘤中的危险信号传导介导，并参与免疫系统。该提案旨在了解放射治疗中不同的剂量分割时间表如何塑造免疫系统。物理剂量输送的最新技术进步鼓励了在较短时间内给予高于常规剂量/分数的创新使用。在人体中产生抗肿瘤而不是促肿瘤免疫应答的最佳剂量尚不清楚，但临床前数据表明，约8 Gy的剂量可能上级。这是通过免疫监测接受大分割和常规方案的前列腺癌患者来解决的问题。该研究以纵向方式设计，以检测个体患者在治疗前、治疗期间和治疗后随时间的变化，并探索其免疫反应的多个方面。为每个病人随时间变化的免疫谱，可以避免一些个体差异的问题。本研究的另一个好处是，将在一个机构中并排比较两种剂量分次方案，从而最大限度地减少潜在偏倚。所采用的方法将基于尖端的、复杂的免疫监测技术，以跟踪效应和抑制淋巴和骨髓源性细胞的频率、表型和功能以及体液应答。包括Dextramer分析、ELISpot、多色流式细胞术、ELISA和多重技术。其目的是描绘一幅全球免疫图景，其中包括肿瘤特异性反应-定性和定量。 定量-在接受放射治疗时对每个患者进行定量。这项研究将产生很大的影响。它可能为重新思考辐射分级、危险信号的释放和肿瘤特异性免疫反应的发展提供新的范例。如果我们要在癌症治疗的背景下参与免疫系统，特别是如果我们要将其与其他更系统性的治疗（包括化疗（CT）和免疫治疗（IT））相结合，那么了解不同的辐射剂量递送时间表如何影响促肿瘤和抗肿瘤免疫反应之间的平衡至关重要。这项研究也有可能产生巨大的影响，作为一个快速的翻译应用，因为它最终将允许我们利用 免疫系统的力量与创新的方法，采取放射肿瘤学到21世纪世纪。

 DESCRIPTION (provided by applicant): Radiation therapy for cancer has systemic consequences that are mediated through danger signaling in irradiated tissues and tumors and that engage the immune system. This proposal aims to understand how different dose-fractionation schedules in radiation therapy shape the immune system. Recent technological advances in physical dose delivery have encouraged innovative use of higher than conventional doses/fraction given over a shorter time. The optimal dose per fraction that generates anti-tumor as opposed to pro-tumor immune responses in humans is not known but preclinical data suggest that doses around 8Gy may be superior. This is the question addressed here by immune monitoring prostate cancer patients receiving hypofractionated and conventional regimens. The study is designed in a longitudinal fashion to detect changes in individual patients over time before, during and after treatment and to probe multiple aspects of their immune responses. Composing immune profiles with time for each patient circumvents some of the problems of individual variation. An additional benefit of this study comes from the fact that both dose-fractionation schedules will be compared side-by-side in one institution, which minimizes potential biases. The methods employed will be based on cutting-edge, sophisticated immune monitoring technologies to track the frequency, phenotype, and function of effector and suppressor lymphoid and myeloid-derived cells as well as humoral responses. They include Dextramer assay, ELISpot, multi-color flow cytometry, ELISA and multiplex technology. The aim is to paint a global immune picture that includes tumor-specific responses - qualitative as well as quantitative - for each patient as they undergo radiation treatment. The study will have high impact. It may provide data for a new paradigm for re-thinking radiation fractionation, the release of danger signals, and the development of tumor-specific immune responses. Knowing how different radiation dose delivery schedules affect the balance between pro- and anti-tumor immune responses is crucial if we are to engage the immune system in the context of cancer treatment, especially if we are to integrate it with other more systemic therapies, including chemo- (CT) and immunotherapy (IT). This study also has the potential to have an enormous impact as a fast-track translational application because it will ultimately allow us to harness the power of the immune system with an innovative approach that takes radiation oncology to the 21st century.