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。我们从肿瘤细胞与树突状细胞融合中提取Hsp70/Hsp90复合物（Hsp70. pc - f），制备了高效的肿瘤疫苗。我们在这项建议中旨在检查疫苗的性质，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与Hsp70结合的作用。PC-F和随后的抗原摄取和递呈到T淋巴细胞。我们的目标是确定SRECI如何在DC中协调抗原交叉呈递、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的作用。PC-F对小鼠自发性乳腺癌的治疗作用。我们的目标是确定治疗效果和疫苗可与佐剂（如TLR3和TLR9激动剂）以及共抑制分子CTLA4抑制剂联合使用的程度。我们将进一步确定疫苗设计是否可以被操纵来选择性地破坏肿瘤起始细胞和放射抵抗细胞，这些细胞在分次放射治疗中积累。

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.