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，尽管这两种现象之间的确切关系仍然模糊不清。在此，我们提供了令人信服的新数据，建立黑素细胞的破坏是必要的维持CD 8记忆T细胞对黑色素瘤的反应。我们发现，在耗尽调节性T细胞和手术切除已建立的黑色素瘤后，自发性白癜风维持黑色素瘤/黑色素细胞Ag特异性记忆T细胞，这些细胞不会在功能上耗尽，并提供长期的肿瘤保护。这些研究建立了自身免疫和长期抗肿瘤免疫之间的因果关系。现在至关重要的是要确定这些长寿的T细胞对癌症的反应的机制。我们假设，自身免疫性疾病提供了一个宿主环境，这是唯一能够永久的T细胞对肿瘤/自身抗原的反应;和组织特异性自身免疫是肿瘤免疫疗法，靶向自身抗原的持久疗效所必需的。我们的第一个具体目标将是确定维持对黑色素瘤/黑素细胞抗原的保护性CD 8 T细胞应答的自身免疫要求。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，目的是恢复功能性记忆T细胞对黑色素瘤的反应。研究将采用B16黑色素瘤和新的BrafV 600 E/Pten-/-诱导转移性黑色素瘤模型，我们最近在C57 BL/6背景下建立了该模型。这项工作将揭示驱动T细胞记忆肿瘤/自身抗原的关键机制，同时建立治疗黑色素瘤的新范式。接下来，特异性目标2将确定最近引发的效应T细胞和皮肤归巢/驻留记忆T细胞如何有助于白癜风宿主的肿瘤免疫。这些研究将调查是否由自身免疫性黑素细胞破坏引发的幼稚T细胞成为能够促进黑色素瘤破坏的全功能效应子。实验还将解决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对肿瘤/自身反应性T细胞如何有效起源、定位和维持自身的理解中的一个主要空白。最后，具体目标3将确定CD 8和CD 4过继性T细胞疗法的长期有效性是否取决于宿主发展白癜风的能力。BrafV 600 E/Pten-/-黑色素瘤模型将用于模拟免疫疗法与分子靶向的BrafV 600 E抑制的组合。这些研究将首次揭示 自身免疫和记忆性CD 4 T细胞对癌症的反应之间的关系。总之，这项工作将提供一个深入和变革性的研究，在以前未被认识的因素与自身免疫宿主增强肿瘤免疫力，导致创新的新的免疫治疗策略的非必需器官的癌症。

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.