Local Radiation as an Adjuvant for Immunotherapy

局部放射作为免疫治疗的辅助剂

• 批准号: 7383133
• 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/7383133
• 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 regression; Disease-Free Survival; Effectiveness; End Point; 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; Numbers; Primary Neoplasm; Process; Prostate carcinoma; Prostatic; Proteins; RNA Interference; Radiation; Radiation therapy; Reporter; Role; Site; Solid Neoplasm; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Thinking; Transgenic Mice; Transgenic Organisms; Tumor Antigens; Tumor Burden; Tumor Immunity; cancer therapy; carcinogenesis; chemokine; concept; in vivo; innovation; intravital microscopy; lymph nodes; malignant breast neoplasm; migration; mouse model; neoplastic cell; novel therapeutics; pre-clinical; radiation effect; 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细胞免疫可以消除较大的肿瘤负担。然而，显著的临床反应 癌症患者和已建立血管肿瘤的小鼠很难用大多数疫苗接种 战略。肿瘤部位免疫细胞的运输和激活不足被认为是至少在 部分，对免疫疗法(IT)未能摧毁实体肿瘤负责。电离放射治疗(RT) 是一种重要的局部癌症治疗方法。作为细胞杀伤剂，RT也可以改变肿瘤 微环境和产生炎症。在转移性乳腺癌的4T1小鼠模型中 RT联合CTLA-4阻断可引起CD8+T细胞介导的反应抑制 转移和诱导原发肿瘤的消退。积累的数据支持RT的假设 可作为免疫佐剂，增强IT的有效性。然而，这一能力 电离辐射促进抗肿瘤免疫仍然存在争议，涉及的机制仍然存在 很大程度上是不确定的。拟议的研究将确定RT促进抗肿瘤的机制 通过分析这一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 使用表达报告抗原的4T1肿瘤模型及其衍生物来确定。介绍 树突状细胞的肿瘤抗原和肿瘤特异性T细胞的激活、扩散和持续 被分析。第二，RT对效应T细胞在肿瘤内的运输和功能的影响将是 下定决心。CXCR6/CXCL16相互作用在CD8+T细胞向照射肿瘤募集中的作用将是 建立了在CXCR6基因座小鼠中使用EGFP敲打信号和RNA干扰沉默CXCL16的方法。在……里面 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放射的反应。第三，RT的能力 联合免疫刺激抗体(抗4-1BB/CD137)诱导抗肿瘤反应 将进行测试，并与CTLA-4封锁进行比较。这些发现将在转基因小鼠身上得到证实。 自发致癌模型。RT可用作免疫学的创新概念 助剂增强信息技术的有效性将开辟一个新的研究领域。总体而言，这些研究将 为在未来的临床试验中测试这一新的治疗策略提供必要的临床前数据。