The Impact of Biologic Aging on Immunity-Related Cervical Cancer Outcome Disparities Among Women Living with HIV in Zambia

生物衰老对赞比亚艾滋病毒感染者免疫相关宫颈癌结果差异的影响

• 批准号: 10754783
• 负责人: Anna Coghill
• 金额: $ 66.64万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754783
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Acute; Affect; Africa South of the Sahara; Age; Age Years; Aging; Biological; Biological Aging; Biological Assay; Biological Clocks; Biological Factors; Biological Markers; Blood; Cancer Center; Cancer Etiology; Cancer Patient; Cells; Cervical Cancer Screening; Chemotherapy and/or radiation; Chronic; Chronology; Clinical; Clinical Data; Clinical Research; Collaborations; DNA; DNA Methylation; DNA analysis; Data; Diagnosis; Disease; Disparity; Elderly; Epidemiology; Epigenetic Process; Flow Cytometry; Future; Geographic Locations; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; Hematology; Hospitals; Human Papillomavirus; Immune; Immune Evasion; Immune System Diseases; Immunity; Immunologics; Immunology; Immunosuppression; Incidence; Income; Individual; Inferior; Knowledge; Life Expectancy; Link; Location; Longevity; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measurable; Measures; Mediating; Morbidity - disease rate; Oncogenic; Oncology; Outcome; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Play; Population; Premature aging syndrome; Prevalence; Process; Radiation Oncology; Recurrence; Regimen; Relapse; Resistance; Role; Sampling; Site; Swab; T-Lymphocyte; Testing; Time; Toxic effect; Translating; Translational Research; Treatment outcome; Treatment-related toxicity; Tumor-infiltrating immune cells; United States; Virus Diseases; Whole Blood; Woman; Work; Zambia; aged; aging population; antiretroviral therapy; bead chip; cancer diagnosis; cancer health disparity; cancer therapy; chemoradiation; clinically relevant; comorbidity; exhaust; health disparity; immune function; low and middle-income countries; methylation pattern; methylome; mortality; mortality risk; multidisciplinary; novel therapeutics; older women; outcome disparities; peripheral blood; receptor; response; side effect; socioeconomics; standard of care; tumor; tumor progression; tumorigenesis; underserved community; women of color

Project Summary/Abstract Cervical cancer disproportionately affects women of color from low-socioeconomic geographical locations. Locations, such as sub-Saharan Africa, can also have a high incidence of Human Immunodeficiency Virus (HIV) infection, and access to cervical cancer screening is generally limited for women living in these underserved communities. Furthermore, People Living with Human Immunodeficiency Virus (PLWH) have evidence of premature aging, which could contribute to cervical cancer progression and responses to chemoradiation therapy (CRT). CRT is the standard of care for locally advanced cervical cancer, and older women (≥52 years of age) treated with CRT have worse side effects than younger (<52 years) women, suggesting that advanced age may influence clinical outcomes from CRT for cervical cancer. Many of the hallmarks of cancer, including tumorigenesis, tumor maintenance, therapy resistance, and immune evasion, are regulated by epigenetic changes in DNA (e.g., DNA methylation). DNA methylation levels are correlated with (1) chronological clocks, which estimate the age of a sample/patient, or (2) biological clocks, a widely accepted measure of where an individual is in their lifespan, regardless of chronological age, which can be reflective of disease morbidity and mortality risk. Indeed, the biological age of PLWH (i.e., HIV-mediated epigenetic age) is advanced up to 20 years beyond chronological age; however, studies examining epigenetic aging in PLWH have not evaluated premature aging in PLWH with cervical cancer, nor the contribution, if any, of oncologic therapy on premature aging. Preliminary data comparing women living with HIV(WHIV) vs. HIV-negative cervical cancer patients indicate that biological aging, defined using patterns of methylation that accumulate on host DNA over time, was significantly accelerated in WHIV vs. HIV-negative cervical cancer patients, and this accelerated aging was significantly associated with mortality after cancer diagnosis. The proposed study will test the hypothesis that a biomarker of aging can be identified and will correlate with systemic and tumor immunologic phenotype and function that can be used, in the future, to select WHIV and cervical cancer for novel therapeutic regimens. In Aim 1, differences in DNA methylation will be compared between WHIV vs. HIV-negative patients with cervical cancer. Aim 2 will focus on measuring systemic and tumor immune cell phenotype, function, and repertoire that will be correlated with biologic age at pre-CRT and 1 year post-CRT. Furthermore, Aim 3 will focus on determining an association of longitudinal (pre-CRT and 1-year post-CRT), biologic age changes with clinical outcomes. Results from the proposed work are expected to elucidate how oncologic treatment in the setting of immunosuppression due to HIV infection impacts the aging process and, through detailed interrogation of immune cells, to link aging to underlying biological features that may exacerbate disparities in clinical outcomes observed in women living with HIV and cervical cancer.

项目摘要/摘要 宫颈癌不成比例地影响低社会经济地理位置的有色女性。 诸如撒哈拉以南非洲之类的位置也可能有大量的人类免疫缺陷病毒（HIV）事件 感染和进入宫颈癌筛查的机会通常受到这些服务不足的女性的限制 社区。此外，患有人类免疫缺陷病毒（PLWH）的人有证据表明 过早衰老，这可能有助于宫颈癌的进展和对化学疗法的反应 （CRT）。 CRT是局部晚期宫颈癌和老年妇女的护理标准（≥52岁） 用CRT治疗的副作用比年轻（<52岁）的女性更差，这表明高龄 影响宫颈癌CRT的临床结果。癌症的许多标志，包括 肿瘤发生，肿瘤维持，耐药性和免疫进化受到表观遗传学的调节 DNA的变化（例如，DNA甲基化）。 DNA甲基化水平与（1）按时间顺序相关， 哪个估计样品/患者的年龄，或（2）生物时钟，这是一个广泛接受的措施 无论年龄段如何 死亡风险。实际上，PLWH的生物年龄（即HIV介导的表观遗传时代）已提高到20年 超出年代年龄；但是，研究PLWH中表观遗传衰老的研究尚未评估过早 患有宫颈癌的PLWH衰老，也不是对早衰的肿瘤学疗法的贡献（如果有的话）。 比较艾滋病毒（WHIV）与HIV阴性宫颈癌患者的妇女的初步数据表明 使用甲基化模式定义的生物衰老，随着时间的推移积聚在宿主DNA上，显着 在WHIV与HIV阴性宫颈癌患者中加速，这种加速衰老显着 与癌症诊断后的死亡率相关。拟议的研究将检验以下假设 可以识别衰老，并将与全身性和肿瘤免疫学表型和功能相关 将来可以使用新型治疗方案选择WHIV和宫颈癌。在AIM 1中，差异 在DNA中，将比较WHIV与HIV阴性患者宫颈癌的甲基化。 AIM 2意志 专注于测量将相关的系统性和肿瘤免疫细胞表型，功能和曲目 在CRT前和CRT 1年的生物年龄。此外，AIM 3将专注于确定关联 纵向（CRT前和1年后CRT）的生物年龄随临床结局而变化。结果 预计拟议的工作将阐明如何在免疫抑制中如何进行肿瘤治疗 HIV感染会影响衰老过程，并通过详细询问免疫细胞，将衰老与 在患有临床结果中的临床结局中可能加剧的生物学特征的基础生物学特征 艾滋病毒和宫颈癌。