Separating autoimmunity and anti-tumor immunity

 描述(申请人提供)：在肿瘤中过表达可诱导的热休克蛋白70(HSP70i)被用作黑色素瘤和其他癌症的免疫治疗的靶点。HSP70i还可以将外部压力转化为自身免疫反应。根据《科学转化医学》杂志的报道，我们在HSP70i中发现了一种负责激活人类树突状细胞(DC)的肽，并开发了HSP70iQ435A，这是一种带有单一氨基酸修饰的突变DNA亚型。由此产生的基因产物支持耐受树突状细胞表型，同时防止甚至逆转T细胞受体转基因小鼠的自身免疫。然而，一旦从耐受环境中移除并过继转移到荷瘤动物体内，来自治疗鼠的T细胞保留了控制黑色素瘤的能力。DNA疫苗接种的小鼠也对抑制肿瘤生长的HSP70i产生了强大的体液反应。在CD8基因敲除小鼠中观察到保护性反应，在过继B细胞转移到肿瘤挑战后，观察到野生型小鼠。我们令人兴奋的初步数据强烈表明，HSP70iQ435A在支持抗肿瘤作用的同时，将抑制自身免疫。肿瘤内的“应激”微环境导致HSP70i的过度表达，从而推动T细胞的募集和对抗HSP70抗体的敏感性，而突变的HSP70支持皮肤的免疫耐受，以防止正常色素细胞的丧失。我们假设HSP70iQ435A极化DC以支持B细胞对肿瘤细胞表达的HSP70i表面的反应，同时阻止MAA反应性T细胞向正常组织的迁移。因此，针对从膜上突出的HSP70i c末端的抗体组合靶向肿瘤，并渗透T细胞，而正常组织细胞由于缺乏HSP70i表面表达和CTL募集减少而不受干扰。我们将测量HSP70iQ435A干预免疫治疗严重副作用(包括移植物抗宿主病)的能力，并揭示HSP70iQ435A不同反应背后的免疫机制，解决治疗对免疫细胞及其靶点的生理和功能的影响。为了进一步研究HSP70iQ435A的应用，我们建立了一个自发性黑色素瘤和白癜风的猪模型。

 DESCRIPTION (provided by applicant): Overexpression of inducible HSP70 (HSP70i) in tumors is exploited as a target for immunotherapy of melanoma and other cancers. HSP70i can also funnel external stress into an autoimmune response. As reported in Science Translational Medicine, we identified a peptide within HSP70i responsible for activating human dendritic cells (DCs) and developed HSP70iQ435A, a mutant DNA isoform with a single amino acid modification. The resulting gene product supports a tolerizing DC phenotype while preventing and even reversing autoimmunity in T cell receptor transgenic mice. T cells from treated mice, however, retain the ability to control melanoma once removed from the tolerizing environment and adoptively transferred into tumor bearing animals. DNA vaccinated mice also develop robust humoral responses to HSP70i that contain tumor growth. Protective responses were observed in CD8 knockout mice, and after adoptive B cell transfer to tumor challenged, wild-type mice. Our exciting preliminary data strongly suggest that HSP70iQ435A will suppress autoimmunity while supporting anti-tumor effects. The 'stressed' microenvironment within tumors leads to HSP70i overexpression that drives T cell recruitment and susceptibility to anti-HSP70 antibodies, whereas mutant HSP70 supports immune tolerance in the skin to prevent loss of normal pigment cells. We hypothesize that HSP70iQ435A polarizes DCs to support B cell responses to HSP70i surface expressed by tumor cells while preventing migration of MAA reactive T cells to normal tissues. Thus tumors are targeted by a combination of antibodies targeting the HSP70i c-terminus protruding from the membrane, and infiltrating T cells, while normal tissue cells are undisturbed through lack of HSP70i surface expression and reduced CTL recruitment. We will measure the ability of HSP70iQ435A to interfere with severe side effects of immunotherapy including graft versus host disease, and unravel the immune mechanism underlying divergent responses to HSP70iQ435A, addressing the consequences of treatment for the physiology and function of immune cells and their targets. A spontaneous swine model of melanoma and vitiligo is included to further the application of HSP70iQ435A.