Human papillomaviruses (HPVs) cause a range of anogenital malignancies and have emerged as major drivers of oropharyngeal cancer (OPC), with a projected annual 30,000 HPV-associated OPC cases in the US alone by 2029. However, the viral antigenic determinants of HPVOPC and intratumoral immune responses are not well studied. Our preliminary data show that the intratumoral immune response encompasses HPV-specific CD8 T cells and B cells, and not only targets the classic HPV oncogenes E6 and E7 but also other viral antigens such as E2. Overall, this project aims to define the immunological landscape of HPV+ OPC in terms of its antigen specificity and cellular composition. This study will provide important insights for the rationale design of novel immunotherapeutic interventions, including therapeutic vaccines, immune checkpoint blockade and adoptive cell therapies.

An increasing number of oropharyngeal cancers (OPCs) is associated with human papillomavirus (HPV) infection, which now accounts for the majority of OPC cases in the US. HPV+ OPC is distinct from HPV- OPC, which is caused by “traditional” carcinogens such as alcohol and tobacco, in that it primarily affects younger individuals and is associated with high cure rates. However, despite HPV status being a known prognostic factor in OPC, readily implementable HPV-specific diagnostics are lacking. In this project, we will build upon our recent observation that tumor-infiltrating B cells from HPV+ OPC patients can be harnessed for the generation of HPV-specific human monoclonal antibodies (hmAbs). We will generate a panel of HPV-specific hmAbs and evaluate their diagnostic potential in standard immunohistochemistry (IHC) applications. This project will not only provide a deeper understanding The successful completion of this study will provide novel highly-specific diagnostic tools for the diagnosis of HPV+ OPC using readily available IHC procedures.

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