Abstract Checkpoint blockade inhibitors (CBI) have revolutionized the care of head and neck cancer (HNC) patients, but overall response rates to CBI remain limited at ~15-20%. This highlights the urgent need to design novel immune oncology (IO) therapies that improve outcome by both overcoming dominant pro-survival pathways in the tumor and reinstating effective, anticancer immunosurveillance. I hypothesize that rationally designed IO therapy, which simultaneously targets key HNC oncogenic signaling pathways and initiates effective anticancer immunosurveillance, is required in order to achieve durable responses. Recent breakthrough discoveries reveal PI3K/mTOR signaling as the most frequently dysregulated network in HNCs, persistently activated in >80% of all HNCs, and that mTOR inhibition acts as a potent antitumor agent in both experimental models of HNC and in a recent Phase 2 clinical trial (NCT01195922). A kinome-wide RNAi screen to identify drivers of aberrant PI3K/mTOR signaling identified persistent HER3 tyrosine phosphorylation in a majority of HNCs. Importantly, the anti-HER3 monoclonal antibody, CDX-3379, which blocks ligand-dependent and -independent functions of both human and murine HER3 imparts potent antitumor activity in PIK3CA wild type HNC murine models and patient-derived xenografts. Preliminary findings demonstrate that tumor rejection downstream from HER3 inhibition (HER3i) necessarily abolishes aberrant PI3K/mTOR signaling, polarizes the tumor microenvironment towards anticancer immunosurveillance and is capable of achieving complete and durable rejection in our novel, recently characterized murine, orthotopic model system of oral cavity, tobacco-signature HNC. My central hypothesis is that HER3 inhibition will potentiate immune checkpoint blockade in HNC to achieve durable response by disrupting PI3K/mTOR oncogenic signaling and reinstating effective cancer immunosurveillance. My central premise is that this novel IO therapeutic platform can serve as the ideal model system in which to explore fundamental tumor-immune dynamics in HNC and address questions regarding immune-escape and resistance to immunotherapy. Additionally, I hypothesize that aberrations along the PI3K/mTOR signaling pathway dictate the clinical relevance of aberrant HER3 signaling and regulate the sensitivity of HNCs to HER3 blockade. My premise here is that examination of the HER3-PI3K/mTOR-immune axis will inform predictions regarding responsiveness to HER3i and identify novel therapeutic targets. To address this and achieve my defined training goals that include broadening my experimental repertoire and expanding collaborative networks, I specifically propose to examine responsiveness of HNCs to HERi by scrutinizing the PI3K/mTOR signaling network and by characterizing fundamental tumor-immune interactions that drive tumor progression.