Molecular Attributes of Tissue Immune Response in HPV Disease

由于对免疫细胞在靶组织中的归巢、功能和滞留机制的不完全理解，免疫疗法的临床成功受到了阻碍。我们的研究团队利用我们独特的临床资源开发新的方法、数据和见解来解决这些基本问题。由人乳头瘤病毒（HPV）引起的上皮内病变（CIN2/3）提供了一个机会来确定免疫反应是如何在非无菌屏障上皮组织中产生和维持的。CIN2/3病变可直接接触，临床无痛，与病毒性癌蛋白E6和E7的功能性专性表达有关。虽然一个亚群经历完全消退，但外周血T细胞对病毒抗原的反应很弱，与疾病结局无关。我们建议研究在CIN2/3中抗原位点隔离的免疫反应机制。我们有一个针对恶性前HPV疾病的积极免疫治疗计划，测试策略以增强T细胞对病毒抗原的反应，并使其能够归巢和进入女性生殖道粘膜。我们已经开发了一系列技术，对研究干预前后获得的人类样本进行定量的、基于组织的分析。该提案基于我们前两个融资周期的成熟数据，包括由三个研究者赞助的ind管理的免疫治疗试验，每个ind都是与NCI RAID项目合作产生的。我们最近的初步数据表明，尽管外周血中检测不到T细胞对疫苗抗原的反应，但系统性治疗性疫苗接种可以在目标病变中诱导显著的效应免疫反应。我们的短期目标是确定这些组织反应的分子特征；确定其免疫治疗相关性；并开发组织特征来预测对治疗性疫苗或直接操作病变微环境的反应可能性。我们的长期目标是开发基于组织的生物标志物的分析算法，为新的治疗策略的开发提供客观的指导，并指导治疗决策。

Clinical success of immunotherapies has been hampered by an incomplete understanding of mechanisms of immune cell homing, function, and retention in the target tissue. Our research team has taken advantage of our unique clinical resources to develop new methods, data, and insights to address these basic questions. Intraepithelial lesions (CIN2/3) caused by human papillomavirus (HPV) present an opportunity to determine how immune responses are generated and maintained in a non-sterile barrier epithelial tissue. CIN2/3 lesions are directly accessible, clinically indolent, and are associated with functionally obligate expression of viral oncoproteins E6 and E7. Although a subset undergo complete regression, peripheral blood T cell responses to viral antigens are weak, and do not correlate with disease outcome. We propose studies to identify mechanisms of immune response sequestered at the site of antigen, in CIN2/3. We have an active immunotherapy program for premalignant HPV disease, testing strategies to enhance T cell responses to viral antigens, and to enable homing and access to the female reproductive tract mucosa. We have developed a constellation of technologies to perform quantitative, tissue-based analyses of human samples obtained before and after study interventions. This proposal is based on maturing data from our two previous funding cycles, including immune therapeutic trials governed by three investigator-sponsored INDs, each of which was generated in collaboration with the NCI RAID program. Our recent preliminary data indicate that systemic therapeutic vaccination can induce a striking effector immune response in the target lesion, despite modest detectable T cell responses to vaccine antigen in the peripheral blood. Our short-term Aims are to identify the molecular signature of these tissue responses; to determine their immune therapeutic relevance; and to develop tissue signatures to predict likelihood of response either to therapeutic vaccination or to direct manipulation of the lesion microenvironment. Our long-term goal is to develop analytic algorithms for tissue-based biomarkers that will provide objective guidelines to inform development of new therapeutic strategies and to guide treatment decisions.