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，并且正在努力降低癌症的发生率，特别是化疗和/或放疗后的复发;研究人员反复寻求增加癌症的免疫原性，以促进宿主抗癌免疫应答。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Foxp 3 + T调节（Treg）细胞在限制抗肿瘤免疫中的作用。因此，降低Treg功能的能力可能具有重要的治疗意义，如果这可以增量地进行并且不需要对维持免疫稳态和预防自身免疫至关重要的TcR的全面消耗。组蛋白/蛋白乙酰转移酶（HAT）通过乙酰化组蛋白尾部促进染色质重塑，但也调节>1750种蛋白质的活性。各种HAT的遗传或药理学靶向对免疫应答的影响在很大程度上是未知的。基于初步数据，我们假设一个或多个HAT将是调节Foxp 3 + Treg功能的关键。因此，我们将调查：目的1）TCLs表达哪些HAT，以及通过遗传和/或药理学方法靶向它们如何影响体外Treg功能？由于初步数据表明HAT、PCAF和p300在控制Treg抑制中的作用，我们将分析这些HAT对调节Treg与非Treg生物学的相对贡献，包括Foxp 3本身的乙酰化。目的2）为了确定从目的1的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依赖性移植耐受的模型，以测试靶向p300或如此涉及的其他HAT是否可以在体内调节Treg功能而不伴随抑制T细胞应答。目的3）为了确定在不消耗Treg的情况下损害Treg功能的策略是否可以增强宿主抗癌免疫应答，我们将通过遗传和药理学方法在肺癌小鼠模型中测试HAT靶向的作用。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，并允许宿主免疫应答减少原发性和复发性肿瘤的生长和扩散。提出的研究将剖析HAT在T细胞中的功能，并测试这些分子是否为操纵免疫应答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，同样可能对HIV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.