Extracellular Hsp70 and hyperthermia in tumor therapy

肿瘤治疗中的细胞外 Hsp70 和热疗

• 批准号: 8685149
• 负责人: STUART Keith CALDERWOOD
• 金额: $ 30.13万
• 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/8685149
• 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; Heat shock proteins; Hyperthermia; 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.

描述（由申请人提供）：细胞外热休克蛋白（HSP）已证明对肿瘤免疫有深远的影响。我们通过从肿瘤细胞和树突状细胞的融合中提取HSP70/HSP90复合物（HSP70.PC-F）来制备高效的癌症疫苗。我们的目标是检查疫苗的特性，并优化其独奏或与电离辐射结合使用。我们首先要了解受体SRECI在树突状细胞（DC）与HSP70.PC-F的结合以及随后摄取和抗原对T淋巴细胞的摄取和表现的作用。我们旨在确定SRECI如何在DC中调节抗原交叉表现，先天免疫刺激和细胞调节。接下来，在AIM 2的翻译研究中，我们将研究HSP70.PC-F在治疗小鼠自发性乳腺癌中的作用。我们旨在确定治疗效果以及可以与TLR3和TLR9激动剂等辅助物结合使用疫苗的程度，以及共抑制分子CTLA4的抑制剂。我们将进一步确定是否可以操纵疫苗设计，以选择在分离放射治疗中积累的肿瘤启动细胞和耐辐射细胞的选择性破坏。