Investigating the Role of Radiation-induced Cell Death in Innate Lymphoid Cell Activation within Unique Tumor Microenvironments

项目概要： 电离辐射作为“原位”疫苗的作用是基于辐射诱导肿瘤释放的能力 活化抗原呈递细胞以引发CD 8 + T细胞的抗原。这介导了“远位效应”， 对一个肿瘤的放射导致远处肿瘤的根除。然而，“远位”的临床报告 这种“效应”是罕见的，可能是因为辐射可以促进免疫抑制细胞的产生。而 放射线用于治疗已经超过世纪，但是对于哪种类型的细胞死亡仍然知之甚少。 是由不同类型的辐射方案诱导的，以及这些细胞死亡机制如何影响细胞的生长。 炎症环境和抗肿瘤免疫。有趣的是，虽然T细胞对凋亡非常敏感，但 组织驻留的先天淋巴样细胞（ILC）是抗辐射的。第1、2和3组ILC被特异性 细胞因子的IL-1家族的成员，其充当组织损伤的“警报”。然而，精确 细胞死亡对IL-1细胞因子释放和下游免疫应答的贡献还不是很好 ILC的特征在于，ILC从未涉及对辐射的免疫应答。因此，建议 实验将通过研究放射治疗诱导的细胞死亡机制如何释放 特异性IL-1家族细胞因子在肿瘤微循环中激活各种ILC亚群（Aim 1）。K99 指导实验将涉及患者衍生的类器官，细胞死亡测定和新的 原位鼠肿瘤模型，以及各种细胞因子的敲除小鼠。目标1的结果将导致 随后的R 00独立阶段研究，以确定辐射诱导的免疫反应 调节抗肿瘤免疫（Aim 2）与放射性肺炎和纤维化（Aim 3）。目标3将建立在我的博士工作产生的IL-22-IRES-BFP报告小鼠，研究这一作用， ILC 3诱导的细胞因子在辐射诱导的纤维化中的作用总的来说，这项研究将产生前所未有的洞察力 辐射诱导的细胞死亡机制和特定的细胞因子如何引导下游免疫反应 临床结果。在R99阶段获得的技术培训和职业发展将有助于 我将启动我的独立研究计划，并为未来的调查揭示更多的问题。结果 从这项工作将作为初步数据的翻译研究，以调查是否有相关性， 辐射诱导的细胞死亡、IL-1细胞因子家族成员的释放、免疫细胞活化和临床 结果。鉴于我在免疫学和放射肿瘤学方面的全面培训和经验，我 独特的定位，利用这两种技能，以解决这些领域的交叉重要问题， 获得对放射治疗疗效的基础机制的基本理解。

PROJECT SUMMARY: The role of ionizing radiation as an “in situ” vaccine is based on radiation’s ability to induce the release of tumor antigens which activate antigen-presenting cells to prime CD8+ T cells. This mediates the “abscopal effect” in which radiation to one tumor leads to eradication of a distant tumor. However, clinical reports of the “abscopal effect” are rare, possibly because radiation can promote the generation of immunosuppressive cells. While radiation has been used therapeutically for over a century, it is still poorly understood which types of cell death are induced by different types of radiation regimens and how these mechanisms of cell death effect the inflammatory milieu and anti-tumor immunity. Interestingly, while T cells are very sensitive to apoptosis, but tissue-resident innate lymphoid cells (ILC) are radioresistant. Group 1, 2 and 3 ILCs are activated by specific members of the IL-1 family of cytokines which serve as “alarmins” of tissue damage. However, the precise contribution of cell death to IL-1 cytokine release and downstream immune responses has not been well characterized, and ILC have never been implicated in the immune response to radiation. Therefore, the proposed experiments will address critical gaps by examining how radiotherapy-induced mechanisms of cell death release specific IL-1 family cytokines in the tumor micorenvironment to activate various ILC subsets (Aim 1). The K99 mentored experiments will involve the integration of patient derived organoids, cell death assays, and novel orthotopic murine tumor models, as well as knockout mice for various cytokines. Results from Aim 1 will lead to subsequent R00 independent phase investigations to determine how radiation-induced immune responses regulate the balance between anti-tumor immunity (Aim 2) and radiation-induced pneumonitis and fibrosis (Aim 3). Aim 3 will build on my doctoral work generating the IL-22-IRES-BFP reporter mouse to study the role of this ILC3-induced cytokine in radiation-induced fibrosis. Collectively, the research will yield unprecedented insight into how radiation-induced cell death mechanisms and specific cytokines direct downstream immune responses and clinical outcomes. The technical training and career development obtained during the R99 phase will help me to launch my independent research program and reveal additional questions for future investigation. Results from this work will serve as preliminary data for a translational study to investigate if there is a correlation between radiation-induced cell death, release of IL-1 cytokine family members, immune cell activation, and clinical outcomes. Given my comprehensive training and experience in both immunology and radiation oncology, I am uniquely positioned to utilize both skillsets to address important questions at the intersection of these fields and gain fundamental understanding of the mechanisms that underlie the efficacy of radiation therapy.