Mechanisms of mucosal immune evasion in high grade cervical dysplasia

高度宫颈不典型增生的黏膜免疫逃避机制

• 批准号: 8037787
• 负责人: Cornelia L Trimble
• 金额: $ 26.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-05 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037787
• 关键词: Adhesions; Agonist; Anogenital venereal warts; Antigens; Biological Markers; Biopsy; Blood Vessels; CD8B1 gene; Cell Adhesion Molecules; Cell Therapy; Cells; Cervical; Cervical Intraepithelial Neoplasia; Cervical dysplasia; Cervix Uteri; Clinical; Clinical Protocols; Clinical Trials; Data; Development; Diagnosis; Disease; Dose; Down-Regulation; Effector Cell; Enrollment; Epithelial; FDA approved; Failure; Funding; Genital system; Gifts; Goals; Heat-Shock Proteins 70; Homeostasis; Homing; Human; Human Papillomavirus; Human papillomavirus 16; Imiquimod; Immune; Immune response; Immunization; Immunologic Surveillance; Immunologics; Immunosuppression; Immunotherapy; Infection; Infiltration; Inflammatory; Institution; Intervention; Lesion; Ligands; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measurement; Measures; Mediating; Memory; Monitor; Mucous Membrane; Nose; Oncogenic; Oral; Patients; Phase; Phenotype; Population; Protocols documentation; Reagent; Recruitment Activity; Reporting; Research Infrastructure; Research Personnel; Route; Screening procedure; Series; Site; Solid Neoplasm; Specificity; Specimen; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Uses; Therapy Clinical Trials; Time; Tissues; Translational Research; United States National Institutes of Health; Vaccination; Vaccines; Viral Antigens; Vulval intraepithelial neoplasia; Woman; Work; base; chemokine; chemokine receptor; cohort; combinatorial; experience; human TLR7 protein; multidisciplinary; peripheral blood; prophylactic; prospective; public health relevance; receptor; receptor expression; response; success; therapeutic vaccine; trafficking

DESCRIPTION (provided by applicant): The goal of this work is to study mechanisms of homing that provide immune surveillance and homeostasis in the genital mucosa. The studies are based on a series of investigator-initiated clinical protocols which are funded by the NIH, testing therapeutic vaccines for the treatment of women with high grade cervical dysplasia (CIN2/3), the lesion which is the immediate precursor to invasive cervical cancer. CIN2/3 is a disease which should be susceptible to an HPV-specific T cell response. The antigenic targets, HPV16 E6 and E7, are non- 'self', and functionally required for disease initiation and persistence. CIN2/3 lesions are relatively accessible, and some of them do regress. The specific hypothesis behind this proposal is that CIN2/3 lesions mitigate the ability of localized immune effector cells to eliminate disease, and that the lesion microenvironment can be manipulated to enable immune-based therapeutic success. This work will analyze clinical specimens from a series of investigator-initiated trials, using therapeutic reagents developed by colleagues at our institution, and manufactured by NCI RAID (pNGVL4a-sig/E7 /HSP70), and as a kind gift from CelticPharma (TA-HPV). The long term goals of this work are to identify mechanisms of immune escape which contribute to the failure of HPV-specific adaptive responses to eradicate CIN2/3, to identify biomarkers predictive of response to immune-based therapies, and to develop combinatorial interventions to uncouple immune escape mechanisms. Specifically, we will: SA1: Determine the homing receptor profile on cervical T cells and expression of corresponding ligands in normal and CIN2/3 mucosa. The characterization of homing mechanisms for cervical mucosa will allow monitoring of immune responses that are likely to traffic to the genital tract, may suggest efficient routes of immunization, e.g., oral or nasal or genital priming, and in cases in which we can determine specificity, may also allow us to estimate the extent to which detectable systemic immune responses correlate with measures in the lesion site. SA2: Determine the immunologic signature of persistent CIN2/3: We will determine the phenotype, functional potential, distribution and co localization of resident immune cell populations in normal cervical mucosa and in CIN2/3, determine the chemokine/chemokine receptor profile associated with presence or absence of CD8+ infiltration in mucosal epithelial and stromal compartments, and determine the chemokine profile at T0 of subjects who respond to vaccination, and of subjects who respond to imiquimod, compared to those who do not. PUBLIC HEALTH RELEVANCE: Mechanisms of mucosal immune evasion in high grade cervical dysplasia The identification of homing mechanisms for genital immune responses in HPV-associated disease is likely to suggest optimal routes of vaccination, to inform monitoring of immune responses likely to traffic to the genital mucosa, and to determine the extent to which immune responses in the cervix can be detected or correlated with measurements in the peripheral blood. From the standpoint of development of T cell therapies for malignancies, because dysplastic cervical lesions are relatively accessible, and mechanisms of lesion- mediated immune suppression common to many human solid tumors are likely to distinguish responders from non-responders, these studies present an opportunity to test proof-of-principle of immune therapeutic combinations.

描述（由申请人提供）：这项工作的目的是研究在生殖器粘膜中提供免疫监测和稳态的归巢机制。这些研究基于一系列由NIH资助的研究者发起的临床方案，该方案测试了治疗高级宫颈发育不良（CIN2/3）女性的治疗疫苗，这是病变，这是侵袭性宫颈癌的直接前体。 CIN2/3是一种疾病，应容易受到HPV特异性T细胞反应的影响。抗原靶标HPV16 E6和E7是非“自我”，在功能上需要疾病的启动和持久性。 CIN2/3病变相对易于访问，其中一些病变会退缩。该提案背后的特定假设是CIN2/3病变可减轻局部免疫效应细胞消除疾病的能力，并且可以操纵病变微环境以实现免疫基于免疫的治疗成功。这项工作将使用我们机构同事开发的治疗试剂，并由NCI RAID（PNGVL4A-SIG /E7 /HSP70）制造，分析一系列研究者发起的试验的临床标本，并作为Celticpharma（TA-HPV）的一种礼物。这项工作的长期目标是确定免疫逃生的机制，这有助于HPV特异性适应性反应消除CIN2/3，以识别预测对基于免疫疗法反应的生物标志物，并开发组合干预措施以取消免疫逃生机制。具体来说，我们将：SA1：确定宫颈T细胞上的归巢受体谱以及在正常和CIN2/3粘膜中相应配体的表达。宫颈粘膜的归巢机制的表征将允许监测可能流行到生殖道的免疫反应，可能表明有效的免疫途径，例如，口服或鼻或鼻或生殖器启动，在我们可以确定特异性的情况下，我们可以估算出与可见的免疫反应的程度相关的程度。 SA2：确定持久性CIN2/3的免疫学特征：我们将确定在正常宫颈粘膜和CIN2/3中，居民免疫细胞种群的表型，功能电位，分布和共同定位，确定趋化因子/趋化因子/趋化因子受体的特征，与CD8+抑制剂在CD8+渗透相关的含量以及磷酸化的含量相关，并确定了搅动的含量，并确定了搅动液的含量，并确定了磷酸化的磷酸化。与未进行疫苗接种的人和对咪喹莫德的反应的受试者相比。 PUBLIC HEALTH RELEVANCE: Mechanisms of mucosal immune evasion in high grade cervical dysplasia The identification of homing mechanisms for genital immune responses in HPV-associated disease is likely to suggest optimal routes of vaccination, to inform monitoring of immune responses likely to traffic to the genital mucosa, and to determine the extent to which immune responses in the cervix can be detected or correlated with measurements in the外周血。从恶性肿瘤的T细胞疗法的发展的角度来看，由于颈颈损伤相对易于访问，并且病变介导的免疫抑制的机制可能是许多人类固体肿瘤所常见的，这些研究可能会将反应者与非响应者区分开，因此这些研究提供了一个机会，可以检验免疫性治疗方法证明的机会。