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

描述（由申请人提供）：我们之前已经证明，表达hsp70的肿瘤细胞死亡具有很强的免疫原性。然而，由于许多黑色素瘤抗原也是正常的黑素细胞分化抗原，抗黑色素瘤免疫往往伴随着自身免疫。为了利用这一点，我们假设，在某些条件下，促炎杀死正常细胞会破坏对该组织正常自身抗原的耐受性，这些自身免疫反应也会针对相关肿瘤的共享抗原。我们发现，热休克蛋白介导的正常黑素细胞杀伤启动了能够清除转移性黑素瘤的自反应性T细胞，但没有明显的自身免疫，因为T细胞反应被调节性T细胞（Treg）迅速抑制。包括额外的T细胞共刺激（CD40L）清除较大的已建立的肿瘤，可能通过控制Treg活性。一旦质粒制造出来，将于2008年春季在梅奥诊所开始对这种方法进行IV期黑色素瘤的临床试验。本应用程序的总体目标是定义和表征自身免疫和抗肿瘤反应之间的免疫连通性，以其他正常细胞类型超越经典的“高度免疫原性”黑素细胞/黑色素瘤范式。为了解决这个问题，我们建立了两种新的自身免疫性疾病模型，其中免疫反应对相同的致病性样损伤（hsp70介导的炎症杀死）是完全不同的。我们的数据显示，自身免疫的病因/严重程度主要取决于先天的、器官特异性的细胞因子对关键启动信号（hsp70）的反应，并可能导致非常多样化的适应性T细胞反应(Th17、前列腺进行性自身免疫或TGF-？-依赖的保护性Treg，在胰腺中)。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。现在，我们将在这些数据的基础上，通过确定前列腺（Specific Aim 1）和胰腺（Specific Aim 2）对hsp70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效应分子/细胞是否与肿瘤排斥介质相同或不同，以及这些效应物是否可以治疗转移性肿瘤，来开发新的肿瘤免疫治疗方法（Specific Aim 3）。这些实验将对包括自身免疫、先天/适应性免疫信号通路和肿瘤免疫学在内的广泛学科具有重要意义，并将推动前列腺癌和可能的胰腺癌的新型免疫治疗临床试验的实施。公共卫生相关性：我们已经证明，在某些条件下，对正常黑素细胞的促炎杀伤可以打破对正常自身抗原的耐受性，并且这些自身免疫反应也针对相关黑素瘤的共享抗原。本应用程序的总体目标是定义和表征自身免疫和抗肿瘤反应之间的免疫连通性，以其他正常细胞类型超越经典的“高度免疫原性”黑素细胞/黑色素瘤范式。为了解决这个问题，我们已经表明，自身免疫的病因/严重程度主要取决于先天的、器官特异性的细胞因子对关键启动信号（hsp70）的反应，并可能导致非常多样化的适应性T细胞反应（前列腺中的Th17，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。我们将以这些数据为基础，更好地了解自身免疫疾病的病因和治疗方法，并通过确定自身免疫的效应分子/细胞与肿瘤排斥介质是否相同或不同，开发肿瘤免疫治疗的新方法。这些实验将对包括自身免疫、先天/适应性免疫信号通路和肿瘤免疫学在内的广泛学科具有重要意义，并将推动前列腺癌和可能的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.