Reprogramming Host Immune Responses to Cure or Control Persistent HPV Infection

描述（由申请人提供）：持续性慢性人乳头瘤病毒（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、宫颈癌、阴茎癌和肛门癌（主要由HPV 16或18引起）;以及口咽癌（HPV 16）。这些疾病的免疫研究都没有解释为什么只有一部分感染了这些普遍存在的HPV的个体不能控制/消除他们的感染。持续活动性感染是HPV诱发恶性肿瘤的主要危险因素。我们已经广泛研究了RRP，其特征在于恶性前肿瘤的反复生长，需要频繁的手术，可能会因完全气道闭塞或癌症而导致死亡，并且每年治疗费用> 1亿美元。我们发现RRP患者具有HPV特异性TH 2样/Treg免疫表型，明显缺乏TH 17样细胞，并且未能释放促炎细胞因子IL-36？由乳头状瘤强烈表达。RRP患者还在气道中组成性地、稳健地表达环氧合酶-2（考克斯-2），其可偏向免疫应答。我们的初步数据显示，塞来昔布（一种考克斯-2抑制剂）治疗可使RRP患者血清TH 2样趋化因子正常化，并导致长期、可持续的临床改善;然而，其机制尚不清楚。我们专注于这种干预策略如何消除/包含持续的HPV感染，我们测试了我们的新假设，即在RRP中重新平衡HPV特异性Treg/TH 17适应性免疫可以消除/控制持续的HPV感染。特异性目的将检验以下假设：通过增强HPV持续感染组织中的TH 17/Treg平衡，可以重新编程容许的、无效的抗HPV免疫应答，导致适应性应答重新极化为TH 1样表型，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？从HPV感染的喉角质形成细胞，以及是否IL-36？可以激活/成熟来自RRP患者的朗格汉斯细胞; 2）确定来自RRP患者的T细胞是否可以通过连接它们的芳烃（AHR）受体而重编程为TH 17样T细胞;和3）确定IL-36诱导的TH 17样T细胞是否可以通过连接它们的芳烃（AHR）受体而重编程为TH 17样T细胞。活化的LC或在连接它们的AHR之后，可以变成HPV特异性的TH 1样T细胞，其可以支持细胞毒性的TC 1样T细胞的产生。这些研究将测试新的概念，即重新调节持续性HPV感染患者的病原体特异性免疫反应，模拟像大多数HPV感染者一样发挥作用，这些人具有潜伏性HPV感染并且没有显示出疾病的迹象。我们正在进行的塞来昔布独特的临床试验允许直接比较体外研究与体内反应，并将为使用这种方法治疗其他持续性HPV感染提供理论依据。这些研究还可以提供关键的和迫切需要的见解，为什么一些感染生殖道和口咽部高危HPV的患者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.