Mechanisms of concomitant tumor immunity and autoimmunity

描述(由申请人提供)：肿瘤免疫和自身免疫之间的联系已经被认识了30多年，尽管这两个现象之间的确切关系仍然含糊其辞。在这里，我们提供了令人信服的新数据，证明黑素细胞的破坏是维持CD8记忆T细胞对黑色素瘤反应所必需的。我们发现，在调节性T细胞耗尽和已建立的黑色素瘤手术切除后，自发性白癜风维持黑色素瘤/黑素细胞抗原特异性记忆T细胞，这些T细胞不会变得功能衰竭，并提供长期的肿瘤保护。这些研究确定了自身免疫和长寿抗肿瘤免疫之间的因果关系。现在，确定这些长寿T细胞对癌症的反应的机制是至关重要的。我们假设，自身免疫性疾病提供了一种宿主环境，这种宿主环境能够保持T细胞对肿瘤/自身抗原的反应；组织特异性自身免疫是靶向自身抗原的肿瘤免疫疗法持久有效所必需的。我们的第一个特定目标将是确定维持对黑色素瘤/黑素细胞抗原的保护性CD8 T细胞反应的自身免疫要求。我们将使用各种方法来释放黑素细胞抗原，杀死黑素细胞，并诱导自身免疫性白癜风，目标是恢复功能性记忆T细胞对黑色素瘤的反应。研究将使用B16黑色素瘤和新的BRAFV600E/Pten-/-可诱导转移性黑色素瘤模型，这是我们最近在C57BL/6背景下建立的。这项工作将揭示驱动T细胞对肿瘤/自身抗原记忆的关键机制，同时建立治疗黑色素瘤的新范式。接下来，特定目标2将确定最近启动的效应器T细胞和皮肤归巢/驻留记忆T细胞如何促进白癜风宿主的肿瘤免疫。这些研究将调查由自身免疫黑素细胞破坏启动的NAéve T细胞是否成为能够促进黑色素瘤破坏的全功能效应器。实验还将讨论T细胞如何进入脱色皮肤和引流淋巴结，控制记忆的建立和对黑色素瘤的长期保护。这项工作有望填补我们在理解肿瘤/自身反应性T细胞如何有效地起源、定位和维持自身方面的一个主要空白。)最后，具体目标3将确定CD8和CD4过继T细胞疗法的长期有效性是否取决于宿主发展成白癜风的能力。BRAFV600E/Pten-/-黑色素瘤模型将被用来模拟结合分子靶向BRAFV600E抑制的免疫治疗。这些研究将首次揭示 自身免疫和记忆CD4T细胞对癌症的反应之间的关系。综上所述，这项工作将提供一个深入和变革性的视角，以了解在具有自身免疫的宿主中肿瘤免疫增强的潜在原因，从而导致非必要器官癌症的创新免疫治疗策略。 公共卫生相关性：这项研究旨在了解癌症的免疫反应，以及如何通过对正常组织的自身免疫反应来改善它们。这些研究集中于癌症新疗法的开发，并确定为什么目前的疗法有效(或缺乏)，因此它们与公共卫生具有广泛的相关性。

DESCRIPTION (provided by applicant): A link between tumor immunity and autoimmunity has been recognized for over 30 years, although the exact relationship between these two phenomena has remained evasive. Herein we provide compelling new data establishing that melanocyte destruction is required for the maintenance of CD8 memory T cell responses to melanoma. We show that, following depletion of regulatory T cells and surgical excision of established melanomas, spontaneous vitiligo maintains melanoma/melanocyte Ag-specific memory T cells that do not become functionally exhausted, and provide long-lived tumor protection. These studies establish a causal relationship between autoimmunity and long-lived anti-tumor immunity. It is now crucial to define the mechanisms underlying these long-lived T cell responses to cancer. We hypothesize that autoimmune disease provides a host environment that is uniquely capable of perpetuating T cell responses to tumor/self antigens; and that tissue-specific autoimmunity is required for the durable efficacy of tumor immunotherapies that target self-antigens. Our first Specific Aim will be to determine the autoimmune requirements for maintaining protective CD8 T cell responses to melanoma/melanocyte antigens. We will use various approaches to release melanocyte antigens, kill melanocytes, and induce autoimmune vitiligo, with a goal of restoring functional memory T cell responses against melanoma. Studies will employ B16 melanoma and the novel BrafV600E/Pten-/- model of inducible metastatic melanoma, which we have recently established on a C57BL/6 background. This work will reveal key mechanisms driving T cell memory to tumor/self antigens, while establishing a new paradigm for the treatment of melanoma. Next, Specific Aim 2 will determine how recently primed effector T cells and skin-homing/resident memory T cells contribute to tumor immunity in hosts with vitiligo. These studies will investigate if na¿ve T cells primed by autoimmune melanocyte destruction become fully functional effectors that are capable of contributing to melanoma destruction. Experiments will also address how T cell access to depigmenting skin and draining lymph nodes governs the establishment of memory and long-lived protection against melanoma. This work is expected to fill a major void in our understanding of how tumor/self-reactive T cells efficiently originate, localize, and sustain themselves.)Finally, Specific Aim 3 will determine if the long-term effectiveness of CD8 and CD4 adoptive T cell therapies is dependent on the host's ability to develop vitiligo. The BrafV600E/Pten-/- melanoma model will be used to model immunotherapy in combination with molecularly- targeted BrafV600E inhibition. These studies will for the first time reveal the nature of the relationship between autoimmunity and memory CD4 T cell responses to cancer. In summary, this work will provide an in-depth and transformative look at previously unappreciated factors underlying enhanced tumor immunity in hosts with autoimmunity, leading to innovative new immunotherapy strategies for cancers of nonessential organs. PUBLIC HEALTH RELEVANCE: This research is aimed at understanding immune responses to cancer and how they can be improved by autoimmune responses to normal tissues. These studies focus on the development of new therapies for cancer, and on determining why current therapies have (or lack) effectiveness, therefore they have broad relevance for public health.