Reprogramming Host Immune Responses to Cure or Control Persistent HPV Infection

描述（由申请人提供）：持续的慢性人乳头瘤病毒（HPV）感染可导致多种疾病，包括复发性呼吸道乳头瘤病（RRP）（通常由HPV 6或11引起）；宫颈上皮内瘤变、宫颈、阴茎和肛门癌（主要由HPV 16或18引起）；以及口咽癌（HPV16）。这些疾病的免疫研究都没有解释为什么只有一小部分感染了这些无处不在的人乳头瘤病毒的个体不能控制/消除他们的感染。持续性活动性感染是hpv诱发恶性肿瘤的主要危险因素。我们广泛研究了RRP，其特点是恶性前肿瘤反复生长，需要频繁手术，可因气道完全闭塞或癌症导致死亡，每年治疗费用为100亿美元。我们发现RRP患者具有HPV特异性th2样/Treg免疫表型，明显缺乏th17样细胞，并且无法释放促炎细胞因子IL-36？由乳头状瘤强烈表达。RRP患者在气道中也组成性地表达环氧化酶-2 (COX-2)，这可能会影响免疫反应。我们的初步数据显示，塞来昔布（一种COX-2抑制剂）治疗可使RRP中血清th2样趋化因子正常化，并导致长期、持续的临床改善；然而，其机制尚不清楚。我们专注于这种介入策略如何消除/抑制持续的HPV感染，并验证我们的新假设，即重新平衡RRP中HPV特异性，Treg/TH17适应性免疫可以消除/控制持续的HPV感染。Specific Aims将验证这样的假设：在HPV持续感染的组织中，通过增强TH17/Treg平衡，一个允许的、无效的抗HPV免疫反应可以被重新编程，从而导致适应性反应向th1样表型重新极化，从而消除活动性疾病。目的是：1)确定IL-36的释放是否需要IL-17 ？人乳头瘤病毒感染喉部角化细胞，IL-36？能激活/成熟RRP患者的朗格汉斯细胞；2)确定来自RRP患者的Tregs是否可以通过连接其芳烃（AHR）受体而被重编程为th17样t细胞；3)确定IL-36是否诱导th17样t细胞？激活的LCs，或其AHR结扎后，可以成为hpv特异性th1样t细胞，可以支持细胞毒性tc1样t细胞的产生。这些研究将测试一个新的概念，即持续HPV感染患者的病原体特异性免疫反应的调节与大多数HPV感染个体的功能相似，这些个体具有潜伏的HPV感染并且没有疾病迹象。我们独特的正在进行的塞来昔布临床试验可以直接比较体外研究和体内反应，并将为使用这种方法治疗其他持续性HPV感染提供依据。这些研究也可以提供关键和迫切需要的见解，为什么一些患者感染了生殖道和口咽部的高风险hpv最终发展为恶性肿瘤。

DESCRIPTION (provided by applicant): Persistent, chronic human papillomavirus (HPV) infection is responsible for multiple diseases including recurrent respiratory papillomatosis (RRP) (usually caused by HPV 6 or 11); cervical intraepithelial neoplasia, cervical, penile and anal cancers (predominantly caused by HPV 16 or 18); and cancers of the oropharynx (HPV16). None of the immune studies of these diseases explain why only a subset of individuals infected with these ubiquitous HPVs fail to contain/eliminate their infection. Persistent active infection i the major risk factor for HPV-induced malignancy. We have extensively studied RRP, characterized by repeated growth of pre-malignant tumors that requires frequent surgeries that can cause mortality due to complete airway occlusion or cancer, and costs >100 million USD to treat/yr. We found that RRP patients have an HPV- specific TH2-like/Treg immunophenotype with a notable absence of TH17-like cells, and a failure to release the pro-inflammatory cytokine IL-36? robustly expressed by papillomas. RRP patients also constitutively, robustly express cyclooxygenase-2 (COX-2) in the airway that can bias immune responsiveness. Our preliminary data show that treatment with celecoxib, a COX-2 inhibitor, normalizes serum TH2-like chemokines in RRP, and causes long-term, sustainable clinical improvement; however, the mechanism is unknown. We focus on how this interventional strategy eliminates/contains persistent HPV infection and we test our novel hypothesis that rebalancing HPV-specific, Treg/TH17 adaptive immunity in RRP may eliminate/control persistent HPV infection. Specific Aims will test the hypothesis that a permissive, ineffective anti-HPV immune response can be reprogrammed through enhancement of the TH17/Treg balance in HPV persistently infected tissues, resulting in re-polarization of the adaptive response toward a TH1-like phenotype that can eliminate active disease. The aims are: 1) Determine whether IL-17 is required for release of IL-36? from HPV-infected laryngeal keratinocytes, and whether IL-36? can activate/mature Langerhans cells from RRP patients; 2) Determine if Tregs from RRP patients can be reprogrammed to become TH17-like T-cells through ligation of their aryl hydrocarbon (AHR) receptor; and 3) Determine if TH17-like T-cells induced by IL-36? activated LCs, or following ligation of their AHR, can become HPV-specific TH1-like T-cells that can support the generation of cytotoxic TC1-like T-cells. These studies will test the novel concept that remodulating pathogen-specific, immune responses of patients with persistent HPV infection simulate to function like most HPV-infected individuals who have latent HPV infection and show no signs of disease. Our unique ongoing clinical trial of celecoxib allows for a direct comparison of in vitro studies with in vivo responses and will provide a rationale to use this approach to treat other persistent HPV infections. These studies could also provide critical and urgently needed insight into why some patients infected with high risk HPVs of the genital tract and oropharynx ultimately develop malignancy.