HAT Inhibition to Impair Foxp3+ Treg Function and Boost Anti-Tumor Immunity

描述（由申请人提供）：癌症是导致死亡的主要原因，正在努力减少癌症的发病率，特别是化疗和/或放疗后的复发；研究人员一再寻求增加癌症的免疫原性，以促进宿主的抗癌免疫反应。这些努力在很大程度上是不成功的，但现在有很多证据表明宿主Foxp3+ T调节细胞（Treg）在限制抗肿瘤免疫中的作用。因此，减少Treg功能的能力可能具有重要的治疗意义，如果这种能力可以逐步完成，而不是全面消耗Treg，这是维持免疫稳态和预防自身免疫所必需的。组蛋白/蛋白乙酰转移酶（HATs）通过使组蛋白尾部乙酰化来促进染色质重塑，同时也调节>1750蛋白的活性。基因或药物靶向各种类型的hat对免疫反应的影响在很大程度上是未知的。根据初步数据，我们假设一个或多个hat将是调节Foxp3+ Treg功能的关键。因此，我们将研究：目标1)Treg表达哪些HATs，以及通过遗传和/或药理学方法靶向它们如何影响Treg体外功能？由于初步数据表明了HATs、PCAF和p300在控制Treg抑制中的作用，我们将分析这些HATs对Treg与非Treg生物学调控的相对贡献，包括Foxp3本身的乙酰化。为了确定从Aim 1研究中获得的体外见解是否可以转化为实际治疗，我们将建立Treg依赖性移植耐受模型，以测试靶向p300或其他相关HATs是否可以在体内调节Treg功能而不同时抑制T细胞反应。目的3)为了确定在不消耗Treg功能的情况下损害Treg功能的策略是否可以增强宿主的抗癌免疫反应，我们将通过遗传学和药理学方法在小鼠肺癌模型中测试HAT靶向的效果。这些在免疫能力强的宿主中的研究将评估HAT靶向是否可以抑制Treg功能，并允许宿主免疫反应抑制原发性和复发性肿瘤的生长和扩散。提出的研究将剖析HATs在Treg中的功能，并测试这些分子是否为操纵免疫反应提供关键的治疗靶点，特别是在需要减少Treg抑制的情况下。因此，我们的研究应该对恶性肿瘤患者免疫治疗新策略的发展产生重大影响，同样也可能对艾滋病毒或其他慢性感染患者的管理产生影响。

DESCRIPTION (provided by applicant): Cancers are a leading cause of death and in efforts to reduce the incidence of the cancer, and especially recurrence after chemotherapy and/or radiation; investigators have repeatedly sought to increase the immunogenicity of cancers so as to promote host anti-cancer immune responses. These efforts have largely been unsuccessful, but much evidence now points to a role of host Foxp3+ T regulatory (Treg) cells in limiting anti-tumor immunity. Hence, the ability to decrease Treg function may be of major therapeutic significance if this can be done incrementally and without full-scale depletion of Tregs that are essential to maintenance of immune homeostasis and prevention of autoimmunity. Histone/protein acetyltransferases (HATs) promote chromatin remodeling by acetylating histone tails but also regulate the activities of >1750 proteins. The effects of genetic or pharmacologic targeting of the various classes of HATs on immune responses are largely unknown. Based upon preliminary data we hypothesize that one or more HATs will be key to regulation of Foxp3+ Treg functions. Accordingly we will investigate: Aim 1) What HATs are expressed by Tregs and how does their targeting by genetic and/or pharmacologic approaches affect Treg function in vitro? Since preliminary data points to roles for the HATs, PCAF and p300, in control of Treg suppression, we will analyze the relative contribution of these HATs to regulation of Treg vs. non-Treg biology, including acetylation of Foxp3 itself. Aim 2) To determine whether the in vitro insights obtained from studies of Aim 1 can translate to actual therapies, we will models of Treg-dependent transplant tolerance to test whether targeting of p300 or other HATs so implicated can regulate Treg functions in vivo without concomitant suppression of T cell responses. Aim 3) To determine whether strategies to impair Treg function without their depletion can boost host anti-cancer immune responses, we will test the effects of HAT targeting through genetic and pharmacologic approaches in murine models of lung cancer. These studies in immunocompetent hosts will assess whether HAT targeting can dampen Treg functions and allow host immune responses to curtail the growth and spread of primary and recurrent tumors. The studies proposed will dissect the functions of HATs in Tregs and test whether these molecules provide key therapeutic targets for manipulation of the immune responses, especially in those circumstances when reduction of Treg suppression is desirable. Hence, our studies should have major consequences for development of new strategies for immunotherapy in patients with malignancies, and likewise may have consequences for management of patients with HIV or other chronic infections. PUBLIC HEALTH RELEVANCE: We will investigate how cancers can grow and spread in individuals despite an intact immune system, focusing on the role of host Foxp3+ T regulatory (Treg) cells in limiting anti-tumor immunity. We will identify the histone/protein acetyltransferase enzymes (HATs) required for Treg function, and test whether HAT inhibition will decrease Treg functions and thereby allow host immune responses to control the growth and spread of tumors. Our studies may identify new therapies for patients with malignancies, and may also have consequences for management of patients with HIV or other chronic infections.