PROJECT 1 – PROJECT SUMMARY/ABSTRACT Project 1. Characterize the Mechanism by Which Papillomaviruses Evade Host Immunity Paul Lambert, Project Leader; Paul Ahlquist and Paul Sondel, Co-Leaders A subset of human papillomaviruses (HPVs) cause 5% of human cancers including the majority of cervical cancers, which is an AIDS-defining malignancy. During the current funding period, we discovered a host factor induced by papillomaviruses that contributes to the ability of this virus to evade host immune responses, allowing it to establish persistent infections that can lead to cancer. This discovery was made using a mouse papillomavirus infection model. Evidence supports the hypothesis that high-risk anogenital HPVs use this same mechanism. We further discovered that this host factor contributes to resistance to immune checkpoint blockade immunotherapy (ICI) in both mouse and human head and neck cancers. In this project we will explore further the mechanisms underlying immune evasion by HPV using a new model for inducible expression of HPV16 oncogenes in immunocompetent mice that better models HPV-induced carcinogenesis in humans, focusing on anal cancer because its frequency of occurrence is increasing, especially amongst people living with HIV (PLWH). During the current funding period, we also discovered that estrogen, which we and others have previously determined contributes to HPV-mediated cervical carcinogenesis, promotes persistent infection by mouse papillomavirus at least in part by suppressing host immunity, leading to increased severity of cervicovaginal neoplasia including cancer in mice. We describe experiments to determine how estrogen affects host immunity, and how to block it to improve response to ICI. The studies described in this project are designed to learn how to convert HPV-associated cancers that tend to be immunologically cold, ICI-unresponsive tumors to immunologically hot, ICI-responsive tumors, with the ultimate goal to translate our findings to the clinic.