Extracellular Hsp70 and hyperthermia in tumor therapy

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有深远的影响。我们通过从肿瘤细胞和树突状细胞(Hsp70.PC-F)融合的肿瘤细胞中提取Hsp70/Hsp90复合体，制备了一种高效的肿瘤疫苗。在这项建议中，我们的目标是检查疫苗的特性，并优化其单独使用或与电离辐射结合使用。我们的目标是首先了解树突状细胞(DC)中受体SRECI在与Hsp70.PC-F结合以及随后抗原摄取和呈递到T淋巴细胞中的作用。我们的目标是确定SRECI如何在DC中协调抗原交叉递呈、先天免疫刺激和细胞调节。接下来，在目标2的翻译研究中，我们将检测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可以在多大程度上与辅助剂如TLR3和TLR9激动剂以及共同抑制分子CTLA4的抑制剂联合使用。我们将进一步确定疫苗设计是否可以被操纵，以选择性地摧毁在分次放射治疗中积累的肿瘤启动细胞和抗辐射细胞。 公共卫生相关性：免疫治疗和放射治疗相结合，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，而免疫治疗能够靶向播散的细胞(转移)的小群体。我们基于从肿瘤中提取热休克蛋白并将其注射到荷瘤小鼠体内，设计了一种具有独特性质的新型疫苗。我们将确定疫苗单独或与生物佐剂和电离辐射联合杀灭小鼠乳腺肿瘤细胞的效果。

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.