Local Radiation as an Adjuvant for Immunotherapy

局部放射作为免疫治疗的辅助剂

• 批准号: 7760656
• 负责人: Sandra Demaria
• 金额: $ 32.21万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760656
• 关键词: Adjuvant; Antibodies; Antigen Presentation; Antigens; Behavior; Breast Carcinoma; CD8B1 gene; CXCR6 gene; Cancer Patient; Carcinoma; Cells; Cellular Immunity; Cessation of life; Clinical; Clinical Data; Clinical Trials; Cross-Priming; Data; Dendritic cell activation; Disease; Disease-Free Survival; Effectiveness; Failure; Fluorescence; Future; Image; Immune; Immune Cell Activation; Immunologic Adjuvants; Immunotherapy; Inflammation; Investigation; Ionizing radiation; Liver; Localized Malignant Neoplasm; Lung; Mammary gland; Mediating; Modeling; Mus; Natural Killer Cells; Neoplasm Metastasis; Primary Neoplasm; Process; Prostate carcinoma; Prostatic; Proteins; RNA Interference; Radiation; Radiation therapy; Reporter; Role; Site; Solid Neoplasm; T cell response; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Tumor Antigens; Tumor Burden; Tumor Immunity; cancer therapy; carcinogenesis; chemokine; in vivo; innovation; intravital microscopy; lymph nodes; malignant breast neoplasm; migration; mouse model; neoplastic cell; novel therapeutics; pre-clinical; receptor; response; trafficking; tumor; uptake; vaccination strategy

CD8+ T-cell mediated immunity can eliminate large tumor burdens. However, significant clinical responses of cancer patients and mice with established vascularized tumors are difficult to achieve with most vaccination strategies. Insufficient trafficking and activation of immune cells at tumor sites are thought to be, at least in part, responsible for the failure of immunotherapy (IT) to destroy solid tumors. Ionizing radiation therapy (RT) is an important local cancer treatment. Used as cytocidal agent, RT can also alter the tumor microenvironment and generate inflammation. In the 4T1 mouse model of metastatic breast cancer we have shown that RT in combination with CTLA-4 blockade elicits a CD8+ T cell-mediated response inhibiting metastases and inducing regression of primary tumors. Accumulated data support the hypothesis that RT can be used as an immunological adjuvant to enhance the effectiveness of IT. However, the ability of ionizing radiation to promote anti-tumor immunity is still controversial, and mechanisms involved remain largely undefined. Proposed studies will determine the mechanismswhereby RT promotes anti-tumor immunity by analyzing the critical steps of this process. First, the ability of RT to promote cross-priming will be determined using the 4T1 tumor model and its derivative expressing a reporter antigen. Presentation of tumor antigens by dendritic cells and activation, dissemination and persistence of tumor-specific T cells will be analyzed. Second, the effect of RT on effector T cell trafficking and function within tumors will be determined. The role of CXCR6/CXCL16 interactions in CD8+ T cell recruitment to irradiated tumors will be established employing EGFP-knockin in the CXCR6 locus mice, and RNA interference to silence CXCL16. In addition, intravital microscopy will be used to study the dynamic behavior of CXCR6+ T cells in the microenvironment of established 4T1 tumors and their response to local radiation. Third, the ability of RT to induce anti-tumor responses in combination with another immune stimulatory antibody (anti-4-1BB/CD137) will be tested and compared to CTLA-4 blockade. Findings will then be confirmed in a transgenic mouse model of spontaneous carcinogenesis. The innovative concept that RT can be used as an immunological adjuvant to enhance the effectiveness of IT will open a new field of investigation. Overall, these studies will provide the pre-clinical data necessary for testing this novel therapeutic strategy in future clinical trials.

CD8+ T 细胞介导的免疫可以消除大量的肿瘤负担。然而，显着的临床反应 大多数疫苗接种很难实现癌症患者和患有血管化肿瘤的小鼠 策略。人们认为，至少在肿瘤部位免疫细胞的运输和激活不足 部分原因是免疫疗法（IT）未能摧毁实体瘤。电离放射治疗 (RT) 是重要的局部癌症治疗方法。作为杀细胞剂，RT 也可以改变肿瘤 微环境并产生炎症。在转移性乳腺癌的 4T1 小鼠模型中，我们发现 结果表明，RT 与 CTLA-4 阻断相结合可引发 CD8+ T 细胞介导的抑制反应 转移并诱导原发肿瘤消退。累积的数据支持以下假设：RT 可用作免疫佐剂以增强IT的有效性。然而，有能力 电离辐射促进抗肿瘤免疫仍存在争议，相关机制仍存在争议 很大程度上未定义。拟议的研究将确定放疗促进抗肿瘤的机制 通过分析该过程的关键步骤来获得免疫力。首先，RT促进交叉启动的能力将 使用 4T1 肿瘤模型及其表达报告抗原的衍生物来确定。介绍 树突状细胞的肿瘤抗原以及肿瘤特异性 T 细胞的激活、传播和持久性将 进行分析。其次，RT 对肿瘤内效应 T 细胞运输和功能的影响将是 决定。 CXCR6/CXCL16 相互作用在 CD8+ T 细胞募集到受辐射肿瘤中的作用将是 在 CXCR6 基因座小鼠中使用 EGFP 敲入，并使用 RNA 干扰来沉默 CXCL16。在 此外，活体显微镜将用于研究 CXCR6+ T 细胞在 已建立的 4T1 肿瘤的微环境及其对局部辐射的反应。三、RT的能力 与另一种免疫刺激抗体（抗 4-1BB/CD137）联合诱导抗肿瘤反应 将进行测试并与 CTLA-4 阻断进行比较。研究结果将在转基因小鼠中得到证实 自发癌变模型。 RT作为免疫学手段的创新理念 增强IT辅助功效将开启一个新的研究领域。总体而言，这些研究将 提供在未来的临床试验中测试这种新型治疗策略所需的临床前数据。