Dissecting Tumor-Immune Interactions in HIV-HPV Co-Infection-Associated Oropharyngeal Cancer using Single Cell Sequencing and Novel Mouse Models

Project Summary/Abstract Oropharyngeal squamous cell carcinoma (OPSCC) has emerged as a significant global health concern, with increasing incidence attributed to human papillomavirus (HPV) infection. Additionally, individuals living with HIV/AIDS (PLWH) face a higher risk of developing OPSCC. Understanding the synergistic relationships between

HIV and oral HPV infection in OPSCC development is critical for advancing prevention, diagnosis, and treatment strategies. CD8+ T cells play a pivotal role in antiviral immunity and tumor surveillance. However, the impact of HIV infection on CD8+ T cells remains largely unexplored. Recently, we have identified an HPV integration

hotspot in the PD-L1 gene, contributing to CD8+ T cell exhaustion. In addition, our single-cell analysis revealed a unique subset of exhausted CD8+ T cells associated with HIV-HPV co-infection in the OPSCC microenvironment. We hypothesize that HIV co-infection induces elevated dysfunction/exhaustion of tumor-

infiltrating lymphocytes (TILs), particularly CD8+ T cells, in the OPSCC microenvironment. As a multi-PI application, combining our expertise in single-cell analysis and functional analysis of HIV mouse models and CD8+ T cells, we will investigate the impact of HIV infection on the immune cell landscape of HPV-positive

OPSCC (Aim 1). Additionally, we will characterize the phenotype and specificity of tumor-infiltrating CD8+ T cell receptors (TCRs) and correlate them with cellular exhaustion status in the context HIV-HPV co-infection (Aim 2). Furthermore, we will establish a novel mouse model that faithfully recapitulates HIV-HPV co-infection in OPSCC

to explore dynamic interactions between viral infection, tumor progression, and CD8+ T cells (Aim 3). Additionally, we will investigate the impact of combined antiretroviral therapy (ART) and immune checkpoint blockade on restoring tumor-reactive CD8+ T cell function and preventing HPV-induced neoplastic growth. This research

aims to enhance our understanding of HIV-HPV co-infection's influence on immune responses and immune evasion in oropharyngeal cancer. Findings may inform novel therapeutic strategies to enhance immune responses and improve clinical outcomes for OPSCC patients living with HIV and have broader implications for

other HPV-associated malignancies.