MEMBRANE UBIQUITIN LIGASE-DRIVEN IMMUNE EVASION IN HPV+ HEAD AND NECK CANCER - 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.