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

项目摘要/摘要 宫颈癌对社会经济地理位置较低的有色人种妇女的影响不成比例。 撒哈拉以南非洲等地也可能是人类免疫缺陷病毒(HIV)的高发区 感染，对于生活在这些服务不足的地区的妇女来说，获得宫颈癌筛查的机会通常有限 社区。此外，携带人类免疫缺陷病毒(PLWH)的人有证据表明 早衰可能导致宫颈癌的进展和对放化疗的反应 (CRT)。放射治疗是局部晚期宫颈癌和老年妇女的标准护理(≥，52岁) 接受CRT治疗的副作用比年轻(52岁)女性更严重，这表明高龄女性可能 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、治疗抵抗和免疫逃避受表观遗传学调控 DNA的变化(例如，DNA甲基化)。DNA甲基化水平与(1)时序时钟相关， 它们估计样本/患者的年龄，或(2)生物钟，这是一种被广泛接受的衡量 个人在其寿命中，而不考虑实际年龄，这可以反映疾病的发病率和 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学年龄)提前到了20岁 超越年龄段；然而，检查PLWH表观遗传老化的研究尚未评估过早 PLWH合并宫颈癌患者的衰老，以及肿瘤治疗对过早衰老的贡献(如果有)。 比较携带艾滋病毒(WHIV)的妇女和艾滋病毒阴性的宫颈癌患者的初步数据表明， 生物老化，用随时间积累在宿主DNA上的甲基化模式来定义，显著 在WHIV与HIV阴性的宫颈癌患者中加速，并且这种加速衰老显著 与癌症诊断后的死亡率有关。这项拟议的研究将检验这样一种假设，即一种生物标志物 衰老可以被识别，并将与系统和肿瘤的免疫表型和功能相关，这可以 在未来，将用于选择艾滋病病毒和宫颈癌作为新的治疗方案。在目标1中，差异 在DNA甲基化方面，将对WHIV和HIV阴性的宫颈癌患者进行比较。目标2将 重点测量系统和肿瘤免疫细胞的表型、功能和将被关联的谱系 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)，生物学年龄随临床结果而变化。调查结果： 拟议的工作有望阐明肿瘤治疗如何在免疫抑制的背景下由于 艾滋病毒感染影响衰老过程，并通过对免疫细胞的详细询问，将衰老与 潜在的生物学特征，可能会加剧女性患者临床结果的差异 艾滋病毒和宫颈癌。

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.