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

研究辐射诱导的细胞死亡在独特的肿瘤微环境中先天淋巴细胞激活中的作用

• 批准号: 10115542
• 负责人: Heather Michelle McGee
• 金额: $ 13.69万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115542
• 关键词: Abscopal effect; Address; Adoptive Transfer; Affect; Albumins; Antigen-Presenting Cells; Antigens; Apoptosis; Biological Assay; CD8-Positive T-Lymphocytes; Cancer Patient; Cell Death; Cells; Clinical; Clinical Trials; Clinical Trials Design; Cytokine Receptors; DNA Damage; DNA Repair; Data; Dendritic Cells; Development; Distant; Equilibrium; Family; Family member; Fibrosis; Foundations; Future; Generations; Genotoxic Stress; Homeostasis; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunooncology; Immunotherapy; Inflammatory; Interleukin-1; Interleukin-18; Internal Ribosome Entry Site; Investigation; Ionizing radiation; Kinetics; Knock-in; Knockout Mice; Knowledge; Lead; Liver; Liver neoplasms; Lymphoid Cell; Lymphopenia; Measures; Mediating; Mentors; Modeling; Molecular; Mus; Necrosis; Normal tissue morphology; Oncology; Organism; Organoids; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phase; Physicians; Positioning Attribute; Pulmonary Fibrosis; Pulmonary Inflammation; Radiation; Radiation Fibrosis; Radiation Oncology; Radiation Pneumonitis; Radiation therapy; Regimen; Regulatory T-Lymphocyte; Reporter; Reporting; Research; Role; Scientist; Stimulus; T cell response; T-Lymphocyte; Technical Expertise; Testing; Therapeutic Uses; Tissues; Training; Travel; Tumor Antigens; Tumor Immunity; Tumor Tissue; Work; anti-tumor immune response; apoptosis in lymphocytes; base; career development; cell type; conditional knockout; cytokine; draining lymph node; ds-DNA; experience; experimental study; fractionated radiation; immune activation; improved; in situ vaccine; inflammatory milieu; insight; interleukin-22; lung injury; member; neoantigens; novel; programs; radiation effect; radiation response; radioresistant; side effect; synergism; translational study; tumor; tumor growth; tumor microenvironment

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.

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 激活抗原呈递细胞以启动 CD8+ T 细胞的抗原，这介导了“远隔效应”。 对一个肿瘤进行放射治疗可以根除远处的肿瘤。然而，“远隔肿瘤”的临床报告。 “效应”很少见，可能是因为辐射可以促进免疫抑制细胞的产生。 辐射用于治疗已有一个多世纪的历史，但人们对哪些类型的细胞死亡仍知之甚少 由不同类型的放射治疗引起，以及这些细胞死亡机制如何影响 炎症环境和抗肿瘤免疫虽然T细胞对细胞凋亡非常敏感，但 组织驻留先天淋巴细胞 (ILC) 具有抗辐射性，可被特定物质激活。 IL-1 细胞因子家族的成员，可作为组织损伤的“警报器”。 细胞死亡对 IL-1 细胞因子释放和下游免疫反应的贡献尚不清楚 特征，并且 ILC 从未涉及辐射的免疫反应。 实验将通过检查放射治疗诱导的细胞死亡机制如何释放来解决关键差距 肿瘤微环境中的特定 IL-1 家族细胞因子可激活各种 ILC 亚群（目标 1）。 指导实验将涉及患者来源的类器官、细胞死亡测定和新颖的整合 原位小鼠肿瘤模型以及各种细胞因子的基因敲除小鼠的结果将导致。 随后的 R00 独立阶段研究以确定辐射如何诱导免疫反应 调节抗肿瘤免疫（目标 2）与放射性肺炎和纤维化（目标 2）之间的平衡 3). 目标 3 将以我的博士工作为基础，生成 IL-22-IRES-BFP 报告小鼠，以研究其作用。 总的来说，这项研究将产生前所未有的见解。 研究辐射诱导的细胞死亡机制和特定细胞因子如何指导下游免疫反应 R99 阶段获得的技术培训和职业发展将有所帮助。 我启动我的独立研究计划并揭示未来调查结果的其他问题。 这项工作将作为转化研究的初步数据，以调查两者之间是否存在相关性 辐射诱导的细胞死亡、IL-1细胞因子家族成员的释放、免疫细胞激活和临床 鉴于我在免疫学和放射肿瘤学方面的全面培训和经验，我是 具有独特的优势，可以利用这两种技能来解决这些领域交叉点的重要问题 对放射治疗功效的机制有基本的了解。