INHIBITION OF A TREG DEUBIQUITINASE, USP7, PROMOTES 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以及化疗和/或放射治疗后的复发，医生和科学家一再寻求提高癌症的免疫原性，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；部分原因可能是宿主Foxp3+T调节(Treg)细胞在限制抗肿瘤免疫反应中的作用。因此，降低Treg功能的能力可能具有重要的治疗意义，如果这可以逐步进行，而不会全面耗尽Treg，这对维持免疫稳态和预防自身免疫是必不可少的。去泛素酶(DUBS)逆转泛素化的影响，从而稳定各种蛋白质的表达，这些蛋白质通常通过蛋白酶体降解。不同DUBS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。使用一种新的筛选方法，我们已经开发出遗传和药理学数据，指出DUB，USP7，在体外和体内控制小鼠Treg抑制的关键作用，而不伴随着抑制保护性T细胞反应。为了突出这些发现的翻译潜力，我们建议使用遗传学和药理学方法来确定USP7抑制在小鼠肺癌模型中的作用。特别是，我们对免疫活性宿主的研究将评估USP7靶向是否可以抑制Treg功能，并允许宿主免疫反应现在限制肿瘤的生长和扩散。我们的研究可能会对恶性肿瘤患者免疫治疗新策略的开发产生重大影响，也可能对艾滋病毒或其他慢性感染患者的管理具有相关性。

 DESCRIPTION (provided by applicant): Cancers are a leading cause of death and in efforts to reduce their incidence, as well as their recurrence after chemotherapy and/or radiation, physicians and scientists have repeatedly sought to increase the immunogenicity of cancers so as to promote host anti-cancer immune responses. These efforts were largely unsuccessful; likely in part because of the role of host Foxp3+ T regulatory (Treg) cells in limiting anti-tumor immune responses. 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 the maintenance of immune homeostasis and for the prevention of autoimmunity. Deubiquitinase enzymes (DUBs) reverse the effects of ubiquitination and thereby stabilize the expression of various proteins that often are otherwise degraded via the proteasome. The effects of genetic or pharmacologic targeting of various DUBs on immune responses are largely unknown. Using a novel screening approach, we have developed genetic and pharmacologic data that point to a key role for the DUB, USP7, in control of murine Treg suppression in vitro and in vivo, without concomitant suppression of protective T cell responses. With a sharp focus on the translational potential of these findings, we propose to determine the effects of USP7 inhibition in murine models of lung cancer, using genetic and pharmacologic approaches. In particular, our studies in immunocompetent hosts will assess whether USP7 targeting can dampen Treg functions and allow host immune responses to now limit the growth and spread of tumors. Our studies could have major consequences for the development of new strategies for immunotherapy in patients with malignancies, and may also have relevance to the management of patients with HIV or other chronic infections.