Project 1: Exploring viral and immunological factors of HPV associated cancers in PLWH and its relation to survival

PROJECT SUMMARY – PROJECT 1 People living with HIV (PLWH) have significantly higher cancer incidence compared to people without HIV for cancers caused by HPV (cervical, vulvar, anal, penile, and oropharyngeal). Altered immunity, not simply immunodeficiency, is one proposed mechanism driving this excess risk and the significantly worse outcomes

observed following a cancer diagnosis compared to individuals without HIV. The tumor viral and immune milieu are likely major factors contributing to these cancer disparities among PLWH. However, few studies have examined the tumor factors (viral and immune) that underlie differences in the cancer burden by HIV

status, information needed to develop improved cancer prevention and treatment strategies for PLWH. Currently there is no optimal method to screen for or treat HPV-related cancers among PLWH in low- and middle- income countries (LMICs), cancers that are increasing in incidence globally. Other than cervical cancer, HPV-

related cancers are understudied among PLWH in sub-Saharan Africa (SSA). Combination strategies of chemoradiation and immunotherapy are transforming cancer care and increasing survival, treatments that may also benefit PLWH. However, little is known of 1) the immune landscape of tumors that develop among PLWH

and 2) the benefit of immunotherapies to improve cancer outcomes among this population. Our overall goal is to inform the development of effective prevention and treatment strategies for HPV-related cancers among PLWH in SSA. We will study the viral and tumor immune factors that are associated with HPV-

cancers and treatment outcomes and propose a multifaceted approach to study both the viral and immune landscape utilizing viral and immune profiling tools and high-dimensional technologies1,2. Specifically, we will: Aim 1: Estimate the attributable fraction of tumors caused by HPV among PLWH and HIV uninfected

patients. This aim tests the hypothesis that PLWH will have a larger diversity of HPV genotypes across all tumor types, a higher proportion of HPV co-infections, and higher proportion of tumors with biologically active HPV compared to HIV uninfected patients. Aim 2: Characterize the tumor immune landscape of HPV-related cancers. This aim tests the hypothesis

that a more suppressive tumor microenvironment will be present in tumors of PLWH compared to HIV uninfected patients and that despite a higher proportion of infiltrating CD8+ T cells, these will be terminally differentiated, exhausted, and dysfunctional. Aim 3: Investigate the association between HIV status and treatment outcomes for HPV-related cancers.

This aim tests the hypothesis that PLWH will have a higher mortality compared to persons without HIV and the tumor microenvironment will be an important determinant of survival outcomes.