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

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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.