Extracellular Hsp70 and hyperthermia in tumor therapy

肿瘤治疗中的细胞外 Hsp70 和热疗

• 批准号: 8394481
• 负责人: STUART Keith CALDERWOOD
• 金额: $ 32.91万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394481
• 关键词: Adjuvant; Agonist; Antigen Presentation; Antigens; Binding; Biological; Breast Carcinoma; CTLA4 gene; Cancer Vaccines; Cells; Cellular Immunity; Combined Vaccines; Complex; Cross Presentation; Dendritic Cells; Fever; Heat shock proteins; Immune; Immunity; Immunotherapy; Inflammation; Ionizing radiation; Lead; Mammary Neoplasms; Mediating; Mus; Natural Immunity; Neoplasm Metastasis; Pathway interactions; Population; Property; Protein Binding; Proteins; Radiation; Radiation therapy; Regulation; Resistance; Role; Signal Transduction; Structure-Activity Relationship; T-Cell Activation; T-Lymphocyte; TLR3 gene; Toll-like receptors; Translating; Treatment Effectiveness; Tumor Immunity; Vaccine Design; Vaccines; base; cancer therapy; extracellular; human TLR3 protein; inhibitor/antagonist; killings; malignant breast neoplasm; neoplastic cell; novel vaccines; programs; receptor; translational study; tumor; uptake; vaccine effectiveness

DESCRIPTION (provided by applicant): Extracellular heat shock proteins (HSP) have been shown to have a profound effect on tumor immunity. We have prepared a highly effective cancer vaccine by extracting Hsp70/Hsp90 complexes from the fusion of tumor cells and dendritic cells (Hsp70.PC-F). We aim in this proposal to examine the properties of the vaccine and optimize its use either solo or combined with ionizing radiation. We aim first to understand the role of the receptor SRECI in dendritic cells (DC) in binding to Hsp70.PC-F and subsequent uptake and presentation of antigens to T lymphocytes. We aim to determine how SRECI can orchestrate antigen cross presentation, innate immune stimulation and cell regulation in DC. Next, in the translational studies in Aim 2 we will examine the role of Hsp70.PC-F in treatment of spontaneous mammary carcinoma in mice. We aim to determine treatment effectiveness and the degree to which vaccines can be used in combination with adjuvants such as TLR3 and TLR9 agonists as well as inhibitors of co-repressing molecule CTLA4. We will further determine whether vaccine design can be manipulated to give selective destruction of tumor initiating cells and radiation resistant cells that accumulate in fractionated radiation therapy. PUBLIC HEALTH RELEVANCE: Immunotherapy and radiation therapy, when combined, may be highly effective in cancer therapy, as radiation can kill the majority of cells in the tumor whie immunotherapy is capable of targeting small colonies of disseminated cells (metastases). We have devised a novel vaccine with unique properties based on extracting heat shock proteins from tumors and injecting them into tumor bearing mice. We will determine the effectiveness of the vaccine in killing mouse mammary tumor cells alone or in combination with biological adjuvants and ionizing radiation.

描述（由申请人提供）：细胞外热休克蛋白（HSP）已被证明对肿瘤免疫具有深远的影响。我们通过从肿瘤细胞和树突状细胞的融合物中提取Hsp70/Hsp90复合物（Hsp70.PC-F），制备了一种高效的癌症疫苗。我们在此提案中的目的是检查疫苗的特性并优化其单独使用或与电离辐射结合使用。我们的目标首先是了解树突状细胞 (DC) 中受体 SRECI 在与 Hsp70.PC-F 结合以及随后摄取和将抗原呈递给 T 淋巴细胞方面的作用。我们的目标是确定 SRECI 如何协调 DC 中的抗原交叉呈递、先天免疫刺激和细胞调节。接下来，在目标 2 的转化研究中，我们将研究 Hsp70.PC-F 在治疗小鼠自发性乳腺癌中的作用。我们的目标是确定治疗效果以及疫苗与 TLR3 和 TLR9 激动剂以及共抑制分子 CTLA4 抑制剂等佐剂联合使用的程度。我们将进一步确定是否可以操纵疫苗设计来选择性破坏在分段放射治疗中积累的肿瘤起始细胞和放射抗性细胞。 公共卫生相关性：免疫疗法和放射疗法相结合，可能在癌症治疗中非常有效，因为放射可以杀死肿瘤中的大多数细胞，而免疫疗法能够针对播散性细胞的小集落（转移）。我们设计了一种具有独特特性的新型疫苗，其基础是从肿瘤中提取热休克蛋白并将其注射到荷瘤小鼠体内。我们将确定疫苗单独或与生物佐剂和电离辐射组合杀死小鼠乳腺肿瘤细胞的有效性。