Autoimmunity and anti tumor immunity outside of the melanocyte/melanoma paradigm

描述（由申请人提供）：我们先前已经表明，表达hsp 70的肿瘤细胞死亡具有潜在的免疫原性。然而，由于许多黑色素瘤抗原也是正常的黑色素细胞分化抗原，因此抗黑色素瘤免疫常常伴随有自身免疫。为了利用这一点，我们假设在某些条件下，正常细胞的促炎性杀伤会破坏对该组织正常自身抗原的耐受性，并且这些自身免疫反应也会靶向相关肿瘤上的共享抗原。我们表明，HSP介导的正常黑色素细胞的杀伤引发了能够清除转移性黑色素瘤的自身反应性T细胞，但没有明显的自身免疫，因为T细胞应答被调节性T细胞（Treg）迅速抑制。包括额外的T细胞共刺激（CD 40 L）清除了较大的已建立的肿瘤，可能是通过控制Treg活性。一旦质粒被制造出来，2008年春天，马约诊所将开始对这种方法治疗IV期黑色素瘤的临床试验。本申请的总体目标是定义和表征在经典的“高免疫原性”黑素细胞/黑色素瘤范例之外的其它正常细胞类型的自身免疫和抗肿瘤应答之间的免疫连接性。为了解决这一问题，我们建立了两种新的自身免疫性疾病模型，其中对相同病原体样损伤（hsp 70介导的炎性杀伤）的免疫反应是完全不同的。我们的数据显示，自身免疫的病因/严重程度关键取决于对关键起始信号（hsp 70）的先天性器官特异性细胞因子应答，并可导致非常多样化的适应性T细胞应答（Th 17、前列腺中的进行性自身免疫或TGF-β-T细胞）。胰腺中的依赖性保护性Treg）。这些模型还揭示了这些组织中自身免疫和抗肿瘤反应之间的密切机制关系。我们现在将在这些数据的基础上，通过确定前列腺（特异性目的1）和胰腺（特异性目的2）对hsp 70介导的炎症杀伤的不同反应的细胞/分子基础，更好地了解自身免疫性疾病的病因和治疗。我们还将通过确定自身免疫的效应分子/细胞是否与肿瘤排斥反应的介质相同或不同以及此类效应分子/细胞是否可以治疗转移性肿瘤来开发肿瘤免疫治疗的新方法（具体目标3）。这些实验将对广泛的学科具有重要意义，包括自身免疫，先天/适应性免疫信号通路和肿瘤免疫学，并将推动前列腺癌和胰腺癌的新型免疫治疗临床试验的实施。 公共卫生相关性：我们已经表明，在某些条件下，正常黑素细胞的促炎性杀伤可以破坏对正常自身抗原的耐受性，并且这些自身免疫反应也靶向相关黑色素瘤上的共享抗原。本申请的总体目标是定义和表征在经典的“高免疫原性”黑素细胞/黑色素瘤范例之外的其它正常细胞类型的自身免疫和抗肿瘤应答之间的免疫连接性。为了解决这一问题，我们已经表明，自身免疫的病因/严重程度严重依赖于先天性，器官特异性细胞因子对关键起始信号（hsp 70）的反应，并可能导致非常多样化的适应性T细胞反应（Th 17，前列腺中的进行性自身免疫，或胰腺中的TGF-2依赖性保护性Treg）。这些模型还揭示了这些组织中自身免疫和抗肿瘤反应之间的密切机制关系。我们现在将在这些数据的基础上更好地了解自身免疫性疾病的病因和治疗，我们将通过确定自身免疫的效应分子/细胞是否与肿瘤排斥的介质相同或不同来开发肿瘤免疫治疗的新方法。这些实验将对广泛的学科具有重要意义，包括自身免疫，先天/适应性免疫信号通路和肿瘤免疫学，并将推动前列腺癌和胰腺癌的新型免疫治疗临床试验的实施。

DESCRIPTION (provided by applicant): We have previously shown that tumor cell death with expression of hsp70, is potently immunogenic. However, since many melanoma antigens are also normal melanocyte differentiation antigens, anti-melanoma immunity is often accompanied by autoimmunity. In order to exploit this, we hypothesized that pro-inflammatory killing of normal cells would, under certain conditions, break tolerance to normal self antigens of that tissue and that these autoimmune responses would also target shared antigens on associated tumors. We showed that hsp- mediated killing of normal melanocytes primes self-reactive T cells able to clear metastatic melanomas but without overt autoimmunity because the T cell response was rapidly suppressed by regulatory T cells (Treg). Inclusion of additional T cell co-stimulation (CD40L) cleared larger established tumors, possibly by controlling Treg activity. A clinical trial of this approach for Stage IV melanoma is due to commence at the Mayo Clinic in the Spring of 2008 once the plasmids have been manufactured. The overall goal of this application is to define, and characterize, the immunological connectivity between autoimmune and anti-tumor responses for other normal cell types beyond the classically `highly immunogenic' melanocyte/melanoma paradigm. To address this, we generated two novel models of autoimmune disease in which the immunological responses, to the same pathogenic-like insult (hsp70-mediated inflammatory killing), are profoundly different. Our data show that the aetiology/severity of autoimmunity depends critically upon innate, organ specific cytokine responses to key initiating signals (hsp70), and can lead to very diverse adaptive T cell responses (Th17, progressive autoimmunity in the prostate, or TGF-?-dependent protective Treg, in the pancreas). These models also reveal a close mechanistic relationship between autoimmune and anti-tumor responses in these tissues. We will now build on these data to gain a better understanding of the aetiology, and treatment, of autoimmune disease by determining the cellular/molecular basis of the different responses of the prostate (Specific Aim 1) and pancreas (Specific Aim 2) to hsp70-mediated inflammatory killing. We will also develop novel approaches to tumor immunotherapy by determining whether the effector molecules/cells of autoimmunity are the same, or different from, mediators of tumor rejection and whether such effectors can treat metastatic tumors (Specific Aim 3). These experiments will have significance to a broad range of disciplines including autoimmunity, innate/adaptive immune signaling pathways and tumor immunology and will drive implementation of novel immunotherapy clinical trials for prostate and, possibly, pancreatic cancer. PUBLIC HEALTH RELEVANCE: We have shown that that pro-inflammatory killing of normal melanocytes can, under certain conditions, break tolerance to normal self antigens and that these autoimmune responses also target shared antigens on associated melanomas. The overall goal of this application is to define, and characterize, the immunological connectivity between autoimmune and anti-tumor responses for other normal cell types beyond the classically `highly immunogenic' melanocyte/melanoma paradigm. To address this, we have shown that the aetiology/severity of autoimmunity depends critically upon innate, organ specific cytokine responses to key initiating signals (hsp70), and can lead to very diverse adaptive T cell responses (Th17, progressive autoimmunity in the prostate, or TGF-2-dependent protective Treg, in the pancreas). These models also reveal a close mechanistic relationship between autoimmune and anti-tumor responses in these tissues. We will now build on these data to gain a better understanding of the aetiology, and treatment, of autoimmune disease, and we will develop novel approaches to tumor immunotherapy by determining whether the effector molecules/cells of autoimmunity are the same, or different from, mediators of tumor rejection. These experiments will have significance to a broad range of disciplines including autoimmunity, innate/adaptive immune signaling pathways and tumor immunology and will drive implementation of novel immunotherapy clinical trials for prostate and, possibly, pancreatic cancer.