Thursday, April 18, 2024
4/18/2024
ABSTRACT Although the risk of breast cancer is decreased among women living with HIV (WLWH) compared to their HIV- counterparts, breast cancer remains the most common non-AIDS-defining malignancy among WLWH. Unfortunately, breast cancer among WLWH is characterized by biologically aggressive disease and poor outcomes. Given the dual burden of HIV and breast cancer in sub Saharan Africa (SSA), clarity regarding the effect of HIV and associated immune dysfunction in the tumor microenvironment (TME) and blood are required to dissect factors associated with cancer development and progression in this population. We hypothesize that HIV infection creates an environment that promotes the evasion of breast cancer cells from immune surveillance, directly through dysregulation of the immune cells and potentially indirectly by modulation of cancer cell molecular profiles. In this project, we will investigate the extent and nature of HIV-associated immune dysfunction in primary tumor tissue and blood biospecimens from HIV+ and HIV- Ugandan women with breast cancer. In Aims 1 and 2 we will identify HIV-related immunosuppressive features in HIV+ women with breast cancer that could promote tumorigenesis and progression by characterizing immune dysfunction using flow cytometry and tissue transcriptomic profiling. We will assess the cellular phenotype of HIV reservoirs in the TME and phenotype immune cell subpopulations at the single-cell level in HIV+ and HIV- women with breast cancer. Finally, in Aim 3, using clinically validated sequencing and transcriptomic assays, we will compare the molecular profile of breast cancer tissue and blood from HIV+ and HIV- women to identify potential HIV-associated features driving increased tumor aggressiveness. We will evaluate the relationship between tumor somatic alterations and HIV status by multidimensional analyses integrating gene expression, copy number alterations, loss of heterozygosity, and mutational biomarkers. We will compare tumor profiles with immune characteristics identified in both the blood and TME for a holistic assessment of HIV-associated features. This proposed study is consistent with a number of high priority topics for HIV research, specifically addressing HIV-associated comorbidities, via an understanding of immune dysfunction. Additionally, we will be strengthening the research training of the workforce required to conduct HIV-related research in SSA.
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