PROJECT SUMMARY Human papillomavirus (HPV) is the causative agent of 5% of all human cancers, including 25% of head and neck squamous cell carcinomas (HNSCCs). HPV-driven disease progression requires both persistent infection and evasion of the host immune response. One mechanism of immune evasion employed by many cancers, including HPV+ HNSCCs, is the downregulation of major histocompatibility complex class I (MHC-I) on the surface of tumor cells. MHC-I antigen presentation is crucial for recognition of tumor cells by CD8+ T cells during the antitumor response and is a major contributor to lack of patient response to immune checkpoint inhibitor therapy. Our lab has previously shown that an E3 ubiquitin ligase upregulated in HPV+ HNSCCs, MARCHF8, ubiquitinates immune surface receptors, including MHC-I, for subsequent degradation. Further, a genome wide CRISPR screen identified genes involved in autophagy, a cellular degradation pathway, as candidates for negative regulators of MHC-I. Based on these findings, I hypothesize that MARCHF8 upregulation by papillomaviruses promotes immune evasion by directing MHC-I for autophagic degradation. To test this hypothesis, I will 1) investigate the mechanism of MARCHF8-mediated MHC-I ubiquitination and degradation via the autophagy pathway and 2) evaluate inhibition of autophagy as a novel treatment for HPV+ HNSCC. With these aims, this project will uncover a mechanism of immune evasion during papillomavirus-induced carcinogenesis.