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

描述(申请人提供)：癌症是导致死亡的主要原因，为了减少癌症的发病率，特别是化疗和/或放射治疗后的复发，研究人员一再寻求增加癌症的免疫原性，以促进宿主抗癌免疫反应。这些努力在很大程度上是不成功的，但现在许多证据表明，宿主Foxp3+T调节细胞(Treg)在限制抗肿瘤免疫方面发挥了作用。因此，降低Treg功能的能力可能具有重要的治疗意义，如果这项工作能够逐步进行，而不会完全耗尽对维持免疫平衡和预防自身免疫至关重要的Treg。组蛋白/蛋白乙酰转移酶(HATS)通过乙酰化组蛋白尾部促进染色质重塑，但也调节&gt；1750蛋白的活性。不同类别的HAT的遗传或药物靶向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：目的1)Tregs表达哪些HAT，它们的基因和/或药物靶向在体外如何影响Treg的功能？由于初步数据表明HATS、PCAF和p300在控制Treg抑制中的作用，我们将分析这些HATS对Treg和非Treg生物学调控的相对贡献，包括Foxp3本身的乙酰化。目的2)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的治疗，我们将建立Treg依赖的移植耐受模型，以测试靶向p300或其他HAT是否可以在不伴随抑制T细胞反应的情况下调节体内的Treg功能。目的3)为了确定在不耗尽Treg功能的情况下抑制Treg功能的策略是否能够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上测试HAT靶向的效果。这些在免疫活性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来抑制原发和复发肿瘤的生长和扩散。建议的研究将剖析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，特别是在那些需要减少Treg抑制的情况下。因此，我们的研究应该对开发恶性肿瘤患者免疫治疗的新策略产生重大影响，同样可能对艾滋病毒或其他慢性感染患者的管理产生影响。 公共卫生相关性：我们将研究癌症如何在免疫系统完整的情况下在个体中生长和扩散，重点是宿主Foxp3+T调节(Treg)细胞在限制抗肿瘤免疫中的作用。我们将确定Treg功能所需的组蛋白/蛋白乙酰转移酶(HATS)，并测试HAT抑制是否会降低Treg功能，从而允许宿主免疫反应控制肿瘤的生长和扩散。我们的研究可能会为恶性肿瘤患者找到新的治疗方法，也可能对艾滋病毒或其他慢性感染患者的治疗产生影响。

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.