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.

项目概要/摘要 宫颈癌对社会经济地位较低的有色人种女性的影响尤为严重。 撒哈拉以南非洲等地区的人类免疫缺陷病毒 (HIV) 发病率也很高 对于生活在服务欠缺地区的妇女来说，感染和获得宫颈癌筛查的机会通常受到限制 此外，人类免疫缺陷病毒感染者 (PLWH) 有证据表明 过早衰老，可能导致宫颈癌进展和对放化疗的反应 (CRT) 是局部晚期宫颈癌和老年女性（≥52 岁）的标准治疗方法。 与年轻（<52 岁）接受 CRT 治疗的女性相比，接受 CRT 治疗的副作用更严重，这表明高龄可能 影响宫颈癌 CRT 的临床结果，包括许多癌症特征。 肿瘤发生、肿瘤维持、治疗抵抗和免疫逃避均受表观遗传调控 DNA 的变化（例如 DNA 甲基化水平）与 (1) 时间时钟相关。 估计样本/患者的年龄，或（2）生物钟，这是一种广泛接受的衡量样本/患者年龄的方法 个体处于其生命周期，无论实际年龄如何，这都可以反映疾病的发病率和 事实上，PLWH 的生物学年龄（即 HIV 介导的表观遗传年龄）提前了 20 岁。 然而，关于 PLWH 表观遗传衰老的研究尚未评估过早年龄 宫颈癌感染者的衰老，以及肿瘤治疗对过早衰老的影响（如果有的话）。 比较感染艾滋病毒 (WHIV) 的女性与艾滋病毒阴性宫颈癌患者的初步数据表明， 生物衰老是通过随着时间的推移在宿主 DNA 上积累的甲基化模式来定义的， 与 HIV 阴性宫颈癌患者相比，WHIV 患者的衰老速度加快，而且这种加速衰老现象显着 与癌症诊断后的死亡率相关。拟议的研究将检验以下假设：生物标志物 衰老可以被识别，并且与全身和肿瘤免疫表型和功能相关，可以 未来可用于选择 WHIV 和宫颈癌的新治疗方案 在目标 1 中，差异。 目标 2 将比较 WHIV 与 HIV 阴性宫颈癌患者之间的 DNA 甲基化。 专注于测量系统和肿瘤免疫细胞表型、功能和相关的全部功能 与 CRT 前和 CRT 后 1 年的生物学年龄此外，目标 3 将侧重于确定关联。 纵向（CRT 前和 CRT 后 1 年）生物年龄随临床结果的变化。 拟议的工作预计将阐明在免疫抑制的情况下如何进行肿瘤治疗 HIV 感染会影响衰老过程，并通过对免疫细胞的详细询问，将衰老与衰老联系起来。 潜在的生物学特征可能会加剧患有该病的女性所观察到的临床结果的差异 艾滋病毒和宫颈癌。