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.

项目总结/摘要 宫颈癌不成比例地影响来自低社会经济地理位置的有色人种妇女。 撒哈拉以南非洲等地区也可能有高的人类免疫缺陷病毒（艾滋病毒）发病率 对于生活在这些服务不足的地区的妇女来说， 社区.此外，人类免疫缺陷病毒（PLWH）感染者有证据表明， 过早衰老，可能导致宫颈癌进展和对放化疗的反应 （CRT）。CRT是局部晚期宫颈癌和老年女性（≥ 52岁）的标准治疗 CRT治疗的副作用比年轻（<52岁）的女性更严重，这表明高龄可能 影响CRT治疗宫颈癌的临床结果。癌症的许多特征，包括 肿瘤发生、肿瘤维持、治疗抗性和免疫逃避都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）时间时钟相关， 其估计样本/患者的年龄，或（2）生物钟，一种广泛接受的测量， 无论实际年龄如何，个体都处于其生命周期中，这可以反映疾病发病率， 死亡风险。事实上，PLWH的生物学年龄（即，艾滋病毒介导的表观遗传年龄）提前至20岁 然而，研究PLWH的表观遗传衰老的研究没有评估过早的 宫颈癌PLWH的衰老，也没有贡献，如果有的话，肿瘤治疗对过早衰老。 将感染艾滋病毒的妇女与艾滋病毒阴性的宫颈癌患者进行比较的初步数据表明， 生物老化，定义为随着时间的推移在宿主DNA上积累的甲基化模式， 与HIV阴性宫颈癌患者相比，WHIV加速老化，并且这种加速老化显著 与癌症诊断后的死亡率相关。这项拟议的研究将检验以下假设： 衰老可以被识别，并将与全身和肿瘤免疫表型和功能相关， 在未来，将用于选择WHIV和宫颈癌的新治疗方案。在目标1中， 将在WHIV与HIV阴性宫颈癌患者之间比较DNA甲基化。目标2将 专注于测量系统和肿瘤免疫细胞的表型，功能和库， 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），生物学年龄变化与临床结局。结果 拟议的工作预计将阐明如何肿瘤治疗的免疫抑制设置，由于 艾滋病毒感染影响衰老过程，并通过详细询问免疫细胞，将衰老与 潜在的生物学特征可能会加剧在患有乳腺癌的女性中观察到的临床结局差异 艾滋病毒和宫颈癌。