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细胞介导的免疫力可以消除巨大的肿瘤负担。但是，大量的临床反应 在大多数疫苗接种时，难以实现患有既定血管化肿瘤的癌症患者和小鼠 策略。至少在 一部分，负责免疫疗法（IT）破坏实体瘤的失败。电离辐射疗法（RT） 是重要的局部癌症治疗方法。 RT用作细胞杀剂，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，我们有 表明RT与CTLA-4封锁结合起来会引起CD8+ T细胞介导的抑制反应 转移和诱导原发性肿瘤的消退。累积数据支持RT的假设 可以用作免疫学辅助物来增强其有效性。但是， 电离辐射以促进抗肿瘤免疫仍然存在争议，涉及的机制仍然存在 在很大程度上不确定。拟议的研究将确定通过RT的机制促进抗肿瘤 通过分析此过程的关键步骤来免疫。首先，RT促进交叉宣传的能力将 使用4T1肿瘤模型及其表达报告抗原的导数确定。介绍 树突状细胞和激活，肿瘤特异性T细胞的激活，传播和持久性的肿瘤抗原将 可以分析。其次，RT对肿瘤中效应的T细胞运输和功能的影响将是 决定。 CXCR6/CXCL16相互作用在CD8+ T细胞募集到辐照肿瘤中的作用将是 在CXCR6小鼠中采用EGFP-KNOCKIN并建立了RNA干扰CXCL16。在 此外，浸润显微镜将用于研究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。第三，RT的能力 诱导抗肿瘤反应与另一种免疫刺激抗体（抗4-1BB/CD137）结合 将进行测试，并将其与CTLA-4封锁进行比较。然后将在转基因小鼠中确认发现 自发致癌的模型。 RT可以用作免疫学的创新概念 增强其有效性的佐剂将开设一个新的调查领域。总体而言，这些研究将 提供在未来临床试验中测试这种新型治疗策略所需的临床前数据。